Multiple Radical Additions

In 3 a coupling occurs to three nuclei (two identical and one different) and in 5 to five equivalent nuclei (figure 6.6). In these experiments no evidence for the radical 1 is found, which is very likely a short-lived species [46]. 

The ESR spectra of 3 and 5 do not provide information on whether the corresponding radical species carry an even number of benzyl groups attached elsewhere on 

A stepwise addition of benzyl radicals could be observed by using the dimer [F(C5H4)C(CF3)2]2 as a radical precursor [9,49]. Every 10 to 20 min, one more radical is added to Cjq and these subsequent additions can be studied in the ESR spectrum. Eor the bulkier 3,5-dimethylphenylmethyl radical only four additions and no formation of the pentaadduct radical could be detected [49]. 

Mass spectrometric investigations of reaction products obtained by multiple radical additions show that up to eight benzyl groups are added to Cjq. If dibenzyl ketone is used as a radical source, up to 15 benzyl groups are added. The addition of methyl radicals leads to products with up to 34 methyl groups attached to Cjq [46]. 

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Although peroxide-decomposition data have to be used with great caution, it can be concluded that double bonds are consumed by radical addition reactions. One can debate whether the unsaturations are consumed by multiple radical addition reactions or via consecutive radical addition/radical transfer sequences. The latter seems most likely, considering the low tendency of alkyl radicals for addition to alkyl-substituted double bonds under these relatively mild conditions. In radical addition reactions of this kind, the stabilisation of radicals due to polar effects is negligible. Experimental studies show that the reactivity is mainly controlled by steric effects [96]. The order of reactivity MNB > DCPD ENB > HD towards radical addition reactions as found by Fujimoto and coworkers [73, 74] is in line with these considerations. 

Harth et al. took advantage of a radical approach to functionalize (macro) alkoxyamines. They used a nonself-polymerizable monomer (maleimide or maleic anhydride) as a radical trap and then succeeded in preventing multiple radical additions. This step is followed in situ by an elimination of the TIPNO nitroxide. Various other radical traps... 

Polymer formation during the Kharasch reaction or ATRA can occur if trapping of the radical (123), by halocarbon or metal complex respectively, is sufficiently slow such that multiple monomer additions can occur. Efficient polymer synthesis additionally requires that the trapping reaction is reversible and that both the activation and deactivation steps are facile. 

In Part 2 of this book, we shall be directly concerned with organic reactions and their mechanisms. The reactions have been classified into 10 chapters, based primarily on reaction type substitutions, additions to multiple bonds, eliminations, rearrangements, and oxidation-reduction reactions. Five chapters are devoted to substitutions these are classified on the basis of mechanism as well as substrate. Chapters 10 and 13 include nucleophilic substitutions at aliphatic and aromatic substrates, respectively, Chapters 12 and 11 deal with electrophilic substitutions at aliphatic and aromatic substrates, respectively. All free-radical substitutions are discussed in Chapter 14. Additions to multiple bonds are classified not according to mechanism, but according to the type of multiple bond. Additions to carbon-carbon multiple bonds are dealt with in Chapter 15 additions to other multiple bonds in Chapter 16. One chapter is devoted to each of the three remaining reaction types Chapter 17, eliminations Chapter 18, rearrangements Chapter 19, oxidation-reduction reactions. This last chapter covers only those oxidation-reduction reactions that could not be conveniently treated in any of the other categories (except for oxidative eliminations). 

We have seen a number of reactions in which alkene derivatives can be polymerized. Radical polymerization (see Section 9.4.2) is the usual process by which industrial polymers are produced, but we also saw the implications of cationic polymerization (see Section 8.3). Here we see how an anionic process can lead to polymerization, and that this is really an example of multiple conjugate additions. 

A general type of chemical reaction between two compounds, A and B, such that there is a net reduction in bond multiplicity (e.g., addition of a compound across a carbon-carbon double bond such that the product has lost this 77-bond). An example is the hydration of a double bond, such as that observed in the conversion of fumarate to malate by fumarase. Addition reactions can also occur with strained ring structures that, in some respects, resemble double bonds (e.g., cyclopropyl derivatives or certain epoxides). A special case of a hydro-alkenyl addition is the conversion of 2,3-oxidosqualene to dammara-dienol or in the conversion of squalene to lanosterol. Reactions in which new moieties are linked to adjacent atoms (as is the case in the hydration of fumarate) are often referred to as 1,2-addition reactions. If the atoms that contain newly linked moieties are not adjacent (as is often the case with conjugated reactants), then the reaction is often referred to as a l,n-addition reaction in which n is the numbered atom distant from 1 (e.g., 1,4-addition reaction). In general, addition reactions can take place via electrophilic addition, nucleophilic addition, free-radical addition, or via simultaneous or pericycUc addition. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

One of the mildest general techniques to extend a carbon chain entails the addition of a carbon-centered radical to an alkene or alkyne. The method for conducting these addition reactions often determines the types of precursors and acceptors that can be used and the types of products that are formed. In the following section, synthetically useful radical additions are grouped into chain and non-chain reactions and then further subdivided by the method of reaction. Short, independent sections that follow treat the addition of carbon-centered radicals to other multiple bonds and aromatic rings and the additions of hete-roatom-centered radicals. 

Addition reactions of carbon radicals to C—O and C—N multiple bonds are much less-favored than additions to C—C bonds because of the higher ir-bond strengths of the carbon-heteroatom multiple bonds. This reduction in exothermicity (additions to carbonyls can even be endothermic) often reduces the rate below the useful level for bimolecular additions. Thus, acetonitrile and acetone are useful solvents because they are not subject to rapid radical additions. However, entropically favored cyclizations to C—N and C—O bonds are very useful, as are fragmentations (see Chapter 4.2, this volume). 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

Intermolecular free-radical additions of stannyl radicals to multiple bonds have emerged as important methods for the preparation of tetraorganostannanes which can be reacted further to afford new C—C bonds through transition metal mediated coupling processes (e.g. Stille coupling). There are numerous examples of this chemistry715-737, and this treatise will focus on a few selected examples. 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Meerwein type arylations involving radical additions to carbon-heteroatom multiple bonds such as in isothiocyanates have been further extended to tandem reactions leading to heterocycles [117, 118]. 

The thiocarbonyl group is excellent for radical addition, which takes place on the sulfur atom and leads to a carbon-centred radical stabilised by the a-sulfur atom. The Barton reaction has enjoyed a great many applications. It mainly involves xanthates and provides many useful processes, such as deoxygenation, decarboxylation, addition to multiple bonds, etc. A number of reviews by Crich et al. have appeared [188, 189], and the most recent is due to Zard [190]. 

Radical cyclizations may occur by different means including hydride-mediated additions, radical addition of RX across a multiple bond and radical addition followed by fragmentation. Of these, the tin hydride mediated addition is the most common. Additionally, radical cyclizations may occur in tandem or three reactions may occur together within the same molecule. 

Figure 35 Radicals addition to carbon nanotubes. For clarity, one substitution with n multiples is illustrated...

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