Addition of radicals

Intramolecular addition reactions are quite common when radicals are generated in molecules with unsaturation in a sterically favorable position. Cyclization reactions based on intramolecular addition of radical intermediates have become synthetically useful, and several specific cases will be considered in Section 10.3.4 of Part B. 

Because they are acrylic monomers, alkyl cyanoacrylate esters still require the addition of radical polymerization inhibitors, such as hydroquinone or hindered phenols, to prevent radically induced polymerization over time [3j. Since basic initiation of alkyl cyanoacrylate monomers is the predominant polymerization mechanism, large quantities of free radical inhibitors can be added, with little or no effect on adhesive performance. 

Chapter 7, Alkenes Reactions and Synthesis—Alkene epoxidation has been moved to Section 7.8, and Section 7.11 on the biological addition of radicals to alkenes has been substantially expanded. 

Addition of radical inhibitors (e.g. duroquinone, galvinoxyl), which will slow up any pathway involving radicals. 

Tabic 1.2 Relative Rate Constants and Regiospecificities for Addition of Radicals... 

The addition of radicals and, in particular, propagating radicals, to unsaturated systems is potentially a reversible process (Scheme 4.46). Depropagation is cntropically favored and the extent therefore increases with increasing temperature (Figure 4.4). The temperature at which the rate of propagation and depropagalion become equal is known as the ceiling temperature (rc). Above Tc there will be net depolymerization. 

Another method of making the lifetime longer in the liquid phase is by adding compounds which, upon addition of radicals, produce long-lived radicals this method is called spin trapping5. 

This is called the SrnI mechanism," and many other examples are known (see 13-3, 13-4,13-6,13-12). The lUPAC designation is T+Dn+An." Note that the last step of the mechanism produces ArT radical ions, so the process is a chain mechanism (see p. 895)." An electron donor is required to initiate the reaction. In the case above it was solvated electrons from KNH2 in NH3. Evidence was that the addition of potassium metal (a good producer of solvated electrons in ammonia) completely suppressed the cine substitution. Further evidence for the SrnI mechanism was that addition of radical scavengers (which would suppress a free-radical mechanism) led to 8 9 ratios much closer to 1.46 1. Numerous other observations of SrnI mechanisms that were stimulated by solvated electrons and inhibited by radical scavengers have also been recorded." Further evidence for the SrnI mechanism in the case above was that some 1,2,4-trimethylbenzene was found among the products. This could easily be formed by abstraction by Ar- of Ft from the solvent NH3. Besides initiation by solvated electrons," " SrnI reactions have been initiated photochemically," electrochemically," and even thermally." ... 

In certain cases, Michael reactions can take place under acidic conditions. Michael-type addition of radicals to conjugated carbonyl compounds is also known.Radical addition can be catalyzed by Yb(OTf)3, but radicals add under standard conditions as well, even intramolecularly. Electrochemical-initiated Michael additions are known, and aryl halides add in the presence of NiBr2. Michael reactions are sometimes applied to substrates of the type C=C—Z, where the co-products are conjugated systems of the type C=C—Indeed, because of the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this... 

MeON=CH(CH2)3CHO with BusSnH and AIBN, for example led to trans-2-(methoxyamino)cyclopentanol in good yield.Addition of radical to the C=N unit of R—C=N—SPh or R—C=N—OBz led to cyclic imines. Radical addition to... 

Entry 5 is an example of the use of fra-(trimethylsilyl)silane as the chain carrier. Entries 6 to 11 show additions of radicals from organomercury reagents to substituted alkenes. In general, the stereochemistry of these reactions is determined by reactant conformation and steric approach control. In Entry 9, for example, addition is from the exo face of the norbornyl ring. Entry 12 is an example of addition of an acyl radical from a selenide. These reactions are subject to competition from decarbonylation, but the relatively slow decarbonylation of aroyl radicals (see Part A, Table 11.3) favors addition in this case. 

Quite apart from such specific physical methods for the detection of radicals, it should be emphasised that more general indications that radical intermediates are involved in a particular reaction are provided by its high susceptibility to the addition of radical initiators (cf. p. 314) or inhibitors (cf. p. 300), and (compared with polar reactions) its relative insusceptibility to change of solvent. 

Despite the enormous importance of dienes as monomers in the polymer field, the use of radical addition reactions to dienes for synthetic purposes has been rather limited. This is in contrast to the significant advances radical based synthetic methodology has witnessed in recent years. The major problems with the synthetic use of radical addition reactions to polyenes are a consequence of the nature of radical processes in general. Most synthetically useful radical reactions are chain reactions. In its most simple form, the radical chain consists of only two chain-carrying steps as shown in Scheme 1 for the addition of reagent R—X to a substituted polyene. In the first of these steps, addition of radical R. (1) to the polyene results in the formation of adduct polyenyl radical 2, in which the unpaired spin density is delocalized over several centers. In the second step, reaction of 2 with reagent R—X leads to the regeneration of radical 1 and the formation of addition products 3a and 3b. Radical 2 can also react with a second molecule of diene which leads to the formation of polyene telomers. 

Based on the data collected in this section, one must conclude that the addition of radicals to dienes is certainly rapid enough to compete against the typical chain-breaking processes and that especially the addition of electrophilic radicals to polyenes appears to bear significant potential. Terminally substituted polyenes are likely to be unsuitable for radical addition reactions due to their lower addition rates and to undesirable side reactions. 

This scheme can be extended by using mixtures of dienes with electron-deficient alkenes such as acrylonitrile. Due to its nucleophilic nature, addition of radical 68 to acrylonitrile is faster than addition to butadiene. The resulting ambiphilic adduct radical then adds to butadiene to form a relatively unreactive allyl radical. Oxidation and trapping of the allyl cation by methanol lead, as before, to products such as 72 and 73, which are composed of four components the radical precursor 67, acrylonitrile, butadiene and methanol (equation 30)17,94. 

Second, nitroxyl radicals, which are generated either by a one-electron oxidation of SENAs (Eq. 1, Scheme 3.98) or by the addition of radical species to silyl nitronates (Eq. 2, Scheme 3.98), are rather stable and, consequently, can act as kinetically independent species. 

HO2, was considered as a reactive intermediate in both cases. The addition of radical scavengers strongly retarded the oxidation of the phosphinate ion confirming the radical type mechanism. It was also demonstrated that the reaction ceased when the catalyst was masked with EDTA. 

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

Addition of radicals to a different unsaturated substrate is an important class of organic reactions. To understand its regiochemistry, one needs to examine the condensed Fukui function (f°) or atomic softness (.v°) for radical attack of the different potential sites within the reactant substrate. We consider now a simple problem summarized in Example 3. 

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