Radical Substitution at Carbon

Nucleophilic radicals carry cation-stabilising groups on the radical carbon, allowing electron density to be transferred from the radical to an electron-deficient heterocycle they react therefore only with electron-poor heterocycles and will not attack electron-rich systems examples of such radicals are CH20H, alkyl-, and acyl-. Substitution by such a radical can be represented in the following general way  

Aryl radicals can show both types of reactivity. A considerable effort (mainly older work) was devoted to substitutions by aryl radicals they react with electron-rich and electron-poor systems at about the same rate but often with poor regioselectivity.  

1 Reactions of heterocycles with nucleophilic radicals The Minisci reaction  

The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyridines, quinolines, diazines, imidazoles, benzothiazoles, and purines are amongst the systems which have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and 7 to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because N-protonation of the heterocycle both greatly increases its reactivity and promotes regioselectivity towards a nucleophilic radical, most of which hardly react at all with 

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The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Free-radical substitution at an aromatic carbon seldom takes place by a mechanism in which a hydrogen is abstracted to give an aryl radical. Reactivity considerations here are similar to those in Chapters 11 and 13 that is, we need to know which position on the ring will be attacked to give the intermediate... 

Secondly, radical substitution at selenium is very effective with stannyl and silyl radicals. In some cases, carbon radicals are also able to make radical substitutions at selenium. 

Allyl radicals substituted at only one of the terminal carbon centers usually react predominantly at the unsubstituted terminus in reactions with nonradicals. This has been shown in reactions of simple dienes such as butadiene, which react with hydrogen bromide, tetrachloromethane or bromotrichloromethane to yield overall 1,4-addition products . The reaction of allyl radicals with hydrogen donors such as thiols or tin hydrides has been investigated and reviewed repeatedly. In most cases, the thermodynamically more favorable product is formed predominantly. This accords with formation of either the higher substituted alkene or the formation of conjugated tt-systems. Not in all cases, however, is the formation of the thermodynamically more favorable product identical to overall 1,4-addition to the diene. In those cases in which allyl radicals are formed through reaction of dienes with tin hydrides or thiols, the... 

Likewise, treatment of alkylbenzenes 211 with (diacetoxyiodo)benzene in the presence of catalytic amounts of molecular iodine and /7-toluenesulfonamide or p-nitrobenzenesulfonamide in 1,2-dichloroethane at 60 °C gives the corresponding (a-acetoxy)alkylbenzenes 212 in generally good yields (Scheme 3.87) [268]. A plausible mechanism for this reaction involves the initial generation of ArS02NH radicals from PhI(OAc)2, I2 and ArS02NH2, which further promote radical substitution at the benzylic carbon [268]. 

Cyclopropanes can be attacked by radicals at either hydrogen or carbon (Scheme 16). Only very reactive radicals such as Cl , CF3 , t-BuO or imidyl radicals can abstract cyclopropane hydrogen atomswhile with less reactive species such as Br or I only S 2 substitution at carbon is observed . ... 

Similar free radical substitution reactions can be effected with bromine (using, e.g., A-bromosuccinimide [NBS]) and, once the halogen is in place, nucleophilic substitution at carbon a to silicon (or indeed, elsewhere) occurs with relative ease. ... 

Alkenes undergo radical substitution at allylic carbons. NBS is used for bromination at allylic carbons (Section 13.9). The mechanism of the reaction is shown on page 574. 

Free-radical substitution processes occur only rarely at carbon but more often at heteroatoms. The stereochemistry of such a process cannot normally be ascertained, however. Tri-valent phosphorus derivatives are perhaps uniquely suitable for such studies since phosphorus is sufficiently stable configurationally, and free radical substitution at phosphorus occurs with ease. 

The name phenylene o-, m-, or p-) is retained for the radical —C5H4—. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals, with the carbon atoms having the free valences being numbered 1,2-, 1,3-, or 1,4-, as appropriate. 

Further evidence for a bromine-bridged radical comes from radical substitution of optically active 2-bromobutane. Most of the 2,3-dibromobutane which is formed is racemic, indicating that the stereogenic center is involved in the reaction. A bridged intermediate that can react at either carbon can explain the racemization. When the 3-deuterated reagent is used, it can be shown that the hydrogen (or deuterium) that is abstracted is replaced by bromine with retention of stereochemistry These results are also consistent with a bridged bromine radical. 

A clear demonstration of the relative importance of steric and resonance factors in radical additions to carbon-carbon double bonds can be found by considering the effect of (non-polar) substituents on the rate of attack of (nonpolar) radicals. Substituents on the double bond strongly retard addition at the substituted carbon while leaving the rate of addition to the other end essentially unaffected (for example, Table 1.3). This is in keeping with expectation if steric factors determine the regiospeeificity of addition, but contrary to expectation if resonance factors are dominant. 

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). 

The cleavage of C—S bonds in C—SO2R anion radicals plays an important role in SrnI tyP processes ". Kornblum and coworkers described a photostimulated electron transfer chain substitution at a saturated carbon where the leaving group is PhSOj ... 

Several functional groups containing carbon-nitrogen double bonds can participate in radical cyclizations. Among these are oxime ethers, imines, and hydrazones.337 Hydrazones and oximes are somewhat more reactive than imines, evidently because the adjacent substituents can stabilize the radical center at nitrogen.338 Cyclization at these functional groups leads to amino- substituted products. 

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