Heteroatom-centered radicals

Other radical reactions not covered in this chapter are mentioned in the chapters that follow. These include additions to systems other than carbon-carbon double bonds [e.g. additions to aromatic systems (Section 3.4.2.2.1) and strained ring systems (Section 4.4.2)], transfer of heteroatoms [eg. chain transfer to disulfides (Section 6.2.2.2) and halocarbons (Section 6.2.2.4)] or groups of atoms [eg. in RAFT polymerization (Section 9.5.3)], and radical-radical reactions involving heteroatom-centered radicals or metal complexes [e g. in inhibition (Sections 3.5.2 and 5.3), NMP (Section 9.3.6) and ATRP (Section 9.4)]. 

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. 

Alkyl radicals, when considered in relation to heteroatom-centered radicals (e.g. r-butoxy, benzoyloxy), show a high degree of chcmo- and rcgiospecificity in their reactions. A discussion of the factors influencing the rate and rcgiospecificity of addition appears in Section 2.3. Significant amounts of head addition arc observed only when addition to the tail-position is sterically inhibited as it is in a,p-disubstituted monomers. For example, with p-alkylacrylates, cyclohexyl... 

Various other heteroatom-centered radicals have been generated as initiating species. These include silicon-, sulfur-, selenium- (see 3.4.3.1). nitrogen- and phosphorus-centered species (see 3.4.3.2). Kinetic data for reactions of these radicals with monomers is summarized in Table 3.10. 

Tabic 3.10 Selected Rate Data for Reactions of Heteroatom-Centered Radicals... 

Importantly, the purple color is completely restored upon recooling the solution. Thus, the thermal electron-transfer equilibrium depicted in equation (35) is completely reversible over multiple cooling/warming cycles. On the other hand, the isolation of the pure cation-radical salt in quantitative yield is readily achieved by in vacuo removal of the gaseous nitric oxide and precipitation of the MA+ BF4 salt with diethyl ether. This methodology has been employed for the isolation of a variety of organic cation radicals from aromatic, olefinic and heteroatom-centered donors.174 However, competitive donor/acceptor complexation complicates the isolation process in some cases.175... 

Addition ofN-, S- and P-Nucleophiles The reaction of nitrones with heteroatom centered nucleophiles has been little investigated and are mainly applied to the synthesis of new heterocyclic systems and stable nitroxyl radicals, containing a heteroatom at the a-carbon atom. 

Interestingly, homolytic substitution at boron does not proceed with carbon centered radicals [8]. However, many different types of heteroatom centered radicals, for example alkoxyl radicals, react efficiently with the organoboranes (Scheme 2). This difference in reactivity is caused by the Lewis base character of the heteroatom centered radicals. Indeed, the first step of the homolytic substitution is the formation of a Lewis acid-Lewis base complex between the borane and the radical. This complex can then undergo a -fragmentation leading to the alkyl radical. This process is of particular interest for the development of radical chain reactions. 

Scheme 2 Reactivity of carbon- and heteroatom-centered radicals towards organoboranes...

Reductive Addition of Heteroatom Centered Radicals to Alkynes and Alkenes... 

R-Y = radical precursor R-A = desired product A-X = radical trap X = heteroatom centered radical R = radical involved in product formation... 

The stability of heteroatom-centered radicals can be defined relative to reference systems sharing the same type of radical center. The stability of nitrogen-centered radicals may, for example, be defined relative to ammonia... 

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. 

The reactivity of heteroatom-centered radicals depends on both thermodynamic factors (stabilities of starting and product radicals and strengths of forming and breaking bonds) and kinetic factors. The electronegativity of the radical-bearing element is an important consideration. For example, radicals such as C1-, RO- and R3N+- are strongly electrophilic, while RjSn- is more nucleophilic. 

Addition and substitution reactions of heteroatom-centered radicals with multiple bonds have been extensively studied and are sometimes preparatively useful.11 This section will briefly consider the addition reactions of H—Y and X—Y reagents (Kharasch reactions) and substitution reactions (Scheme S6).245... 

The following introduction will briefly recount some of the key features of radical cyclizations with an emphasis on basic concepts that control regio- and stereo-selectivity. More details will be provided in the following sections, which describe specific types of reactions. The factors affecting the cyclization reactions to carbon-heteroatom multiple bonds are treated separately in Section 4.2.5, and the cyclizations of heteroatom-centered radicals are contained in Section 4.2.4. 

In the reduction of radicals by ET, simple carbanions are practically never formed, and one-electron reduction of a carbon-centered radicals is only effective if the electron can be accommodated by the substituent, e.g., a carbonyl group [reaction (24), whereby upon electron transfer the enolate is formed (Akhlaq et al. 1987)]. Thus, in their reduction reactions these radicals react like heteroatom-centered radicals despite the fact that major spin density is at carbon. 

When the binding energy of a hydrogen to a heteroatom is weak, heteroatom-centered radicals are readily produced by H-abstraction or one-electron oxidation followed by H+ loss. Typical examples are phenols (e.g vitamin E in non-aqueous media), tryptophan and related compounds and thiols. Deprotonation of radical cations is indeed often a source of heteroatom-centered radicals even if a deprotonation at carbon or OH addition upon reaction with water would be thermodynamically favored. The reason for this is the ready deprotonation at a heteroatom (Chap. 6.2). 

A common feature of heteroatom-centered radicals is that they react reversibly, only slowly or not at all with 02 (Schuchmann and von Sonntag 1997), and this property is shared by the purine radicals G and A (Chap. 10.2). 

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