Nucleophilic substitutions, radical-mediated

As indicated in Chapter 8, the production of alkanes, as by-products, frequently accompanies the two-phase metal carbonyl promoted carbonylation of haloalkanes. In the case of the cobalt carbonyl mediated reactions, it has been assumed that both the reductive dehalogenation reactions and the carbonylation reactions proceed via a common initial nucleophilic substitution reaction and that a base-catalysed anionic (or radical) cleavage of the metal-alkyl bond is in competition with the carbonylation step [l]. Although such a mechanism is not entirely satisfactory, there is no evidence for any other intermediate metal carbonyl species. 

The anion of methyl phenylacetate, formed by an electrogenerated base, was homocoupled with iodine or anodically mediated by iodide to afford dimethyl 2,3-diphenylsuccinate in high yield and high d, /-selectivity. This reaction probably does not involve free radicals but an iodination-nucleophilic substitution sequence [194,195]. 

The relative extent of dialkylation depends on the electrophilicity of RX (and the nucleophilicity of AR ) when a realtively fast SET (AE i/2 < 0.5 V) is the primary reaction. Other mechanisms may also satisfactorily explain the distribution of products. For instance, adduct formation between the alkyl radical and the mediator (acting as a radical trap) is possible and must be considered in such a case, further reduction of AR may take place, either by electron transfer or by abstraction of a hydrogen atom from the solvent. However, let us keep in mind that radical anions or dianions may act as nucleophiles, since a partial inversion of configuration of some optically active secondary RX compounds has been found [222] after workup under experimental conditions similar or identical to those of the electrolyses. Table 8 exemplifies alkylation reactions following a SET. The reaction scheme may be complicated by the fact that reduced forms of the mediator may act as a reducing nucleophile toward RX. The SET may then be assumed as the rate-determining step in aliphatic nucleophilic substitutions [223], and/or R generated in solution may be added to an electrophilic mediator, such as an activated ketone [224]. 

As it is well known, nucleophilic substitution of a C-X bond, one of the key synthetic reactions with aliphatic compounds is severely limited with aromatic derivatives, where it occurs thermally only with electron-withdrawing substituted compounds and/or under severe conditions. Alternatives include time honored reactions involving the phenyl radical generated by decomposition of diazonium salts after a reductive step, such as the Meerwein and the Gomberg-Bachmann reactions, as well as the (often photoinitiated) SrnI reaction, where a (usually weak, e.g. carbon-iodine) bond is cleaved after monoelectronic reduction to give an aryl radical as the active inter-mediate that adds to an enolate, cyanide or other nucleophiles (and thus again with an aryl radical as the key intermediate. Scheme S). ... 

Pioneering work by Kita demonstrated that SET from electron-rich aromatic rings to phenyUodine(III) bis(trifluoroacetate) generates a radical cation which can be attacked by nucleophilic species with concomitant transfer of a second electron to the iodine species. Rearomatization by deprotonation yields the aromatic substitution prodnct. While this particular methodology does not fit the model for this review since the bond-forming event is ionic in nature, extensions and modifications do proceed through a radical-mediated C—H activation reaction and will be discussed below. 

Electron transfer from the alkene leads to a radical cation that can undergo coupling (Scheme la). The radical cation can also react with the nucleophilic heteroatom of a reagent to afford addition or substitution products (Scheme lb). Adducts can be likewise obtained by oxidation of the nucleophile to a radical that undergoes radical addition. Reactions between alkenes and nucleophiles can be realized too with chemical oxidants that are regenerated at the anode (mediators) (see Chapter 15). Finally, cycloadditions between alkenes can be initiated by a catalytic anodic electron transfer. These principal reaction modes are subsequently illustrated by selected conversions. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

For oxidations, the cation radicals of aromatic compounds like 9,10-diphenyl-antracene, thiantrene, phenoxathiine, or dibenzodioxine are likely candidates. Their reactivity towards nucleophiles, however, limits their application to media of low nucleophilicity. Sometimes the stability of such cation radicals can be enhanced through blocking the reactive positions by substituents. For example, para-substituted triarylamines deliver cation radicals with often excellent stability even in methanol. The stability is further increased by incorporation of urzAu-substituents. Other mediators which have been applied in indirect electrosyntheses are those which are able to abstract hydrogen atoms or hydride atoms. 

Pyrrole anion is unreactive in liquid ammonia under irradiation with PhBr or 1-chloro-naphthalene. However, the reactions of aryl chlorides (p-chlorobenzonitrile, 3- and 4-chloropyridines and 4-chlorodiphenyl sulphone) with 2,5-dimethylpyrrole anion under electrochemical inducement in the presence of a redox mediator gave the C3-substituted product in moderate yields (35-40%) (equation 120)225. The rate constant of the coupling reaction between this nucleophile and aryl radicals is about 5-8 x 109 M"1 s 1 determined by electrochemical methods225. 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

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