Radicals chain nucleophilic substitutions

The ability of a nitro group in the substrate to bring about electron-transfer free radical chain nucleophilic substitution (SrnI) at a saturated carbon atom is well documented.39 Such electron transfer reactions are one of the characteristic features of nitro compounds. Komblum and Russell have established the SrnI reaction independently the details of the early history have been well reviewed by them.39 The reaction of p-nitrobenzyl chloride with a salt of nitroalkane is in sharp contrast to the general behavior of the alkylation of the carbanions derived from nitroalkanes here, carbon alkylation is predominant. The carbon alkylation process proceeds via a chain reaction involving anion radicals and free radicals, as shown in Eq. 5.24 and Scheme... 

Radical chain nucleophilic substitution of heterocycles 91MI39. 

Russell and coworkers62,109,110 have shown that simple enolates undergo free radical-chain nucleophilic substitution reactions with a-chloronitroalkanes by an SRN2 rather than an S l mechanism, and competition with a chain dimerization process was also observed. Using two equivalents of the enolate anion in the reaction allows complete elimination of HN02 to yield a,/i-unsaturated ketones. The synthetic potential of these reactions has also been reported110. 

Formation of heterocyclic rings may be accomplished by electrochemically induced SRN1 reactions136,137 [Eqs. (63)—(66)]. A requirement for such radical-promoted nucleophilic substitutions to proceed as a chain reaction is that the product anion-radical ArNu- be able to transfer an electron to the substrate [Eq. (65)] the oxidation potential of ArNu7 should thus be more negative than the reduction potential of ArX. 

At room temperature under photostimulation a-nitrosulfones react with a variety of nucleophiles via radical anion chain reactions interestingly, in none of the cases where the PhSOj group is involved in SrnI type of substitution does the O end of the ambident anion " play a role. This strong regioselectivity is reminiscent of the one reported for other ambident anions involved in these radical chain substitutions. ... 

The fonnation of these substances contradicts common ideas on nucleophilic substitution. The presence of radical traps (oxygen or tetrabromobenzoquinone) decelerates the formation of both unexpected compounds and product of thioarylation. Consequently, the first stage of the reaction depicted in Scheme 4.5 produces phenylthiyl radical and anion-radical of the substrate. Both electron-transfer products undergo further conversions The phenylthiyl radical gives diphenyldi-sulfide, and the anion-radical of the substrate produces 9-fluorenyl radical. The latter reacts in two directions—dimerizing, it forms bifluorenyl reacting with the nucleophile, it gives the anion-radical of the substitution product. The chain continues because the electron from the anion-radical is transferred to the unreacted molecule of the substrate. The latter loses bromine and then reacts with the nucleophile, and so on (Scheme 4.6). 

The mechanism of the reaction depicted in Scheme 4.6 differs from the Sf.,1 or Sf.,2 mechanism in that it involves the stage of one-electron oxidation-reduction. The impetus of this stage may be the easy detachment of the bromine anion followed by the formation of fluorenyl radical. The latter is unsaturated at position 9 near three benzene rings that stabilize the radical center. The radical formed is intercepted by the phenylthiolate ion. This leads to the anion-radical of the substitution product. Further electron exchange produces the substrate anion-radical and final product in its neutral state. The reaction consists of radical (R)-nucleophilic (N) monomolecular (1) substitution (S), with the combined symbol Sj j l. Reactions of Sj j l type can have both branch-chain and nonchain characters. 

Spin traps can act as one-electron oxidizers. This property is even more pronounced in the interactions of traps with anion-radicals. Traps can block the ion-radical pathway. In other words, they inhibit the whole reaction, including the ion-radical step. This can be explained by both the oxidation of substrate anion-radical and chain termination due to oxidation of product anion-radical. An illustrative example is the inhibition of nucleophilic substitution of 2-chloroquinoxaline by the radical trap bis(tcrt-butyl)nitrone (Carver et al. 1982). 

The revealed mechanism of ter Meer reaction is well-founded. It helps us to understand the peculiarities of nucleophilic substitution reactions having the chain ion-radical mechanism and involving the interaction of radicals with anions at the chain propagation steps. It also demonstrates how the knowledge of kinetics and mechanism can be used to find new ways of initiating and optimizing the reactions important for technical practice. The ter Meer reaction turns out to be a reaction having one name and mechanism. This differs from, say, aromatic nitration, which has one name bnt different mechanisms. 

Swartz and Stenzel (1984) proposed an approach to widen the applicability of the cathode initiation of the nucleophilic substitution, by using a catalyst to facilitate one-electron transfer. Thus, in the presence of PhCN, the cathode-initiated reaction between PhBr and Bu4NSPh leads to diphe-nydisulfide in such a manner that the yield increases from 10 to 70%. Benzonitrile captures an electron and diffuses into the pool where it meets bromobenzene. The latter is converted into the anion-radical. The next reaction consists of the generation of the phenyl radical, with the elimination of the bromide ion. Since generation of the phenyl radical takes place far from the electrode, this radical is attacked with the anion of thiophenol faster than it is reduced to the phenyl anion. As a result, instead of debromination, substitution develops in its chain variant. In other words, the problem is to choose a catalyst such that it would be reduced more easily than a substrate. Of course, the catalyst anion-radical should not decay spontaneously in a solution. 

The first stage of the synthesis involves the interaction of a nitro compound with sodium sulfide. When used alone, sodium sulfide is only slightly effective The reactions proceed slowly and the yields of mercaptanes are small. If elemental sulfur is added, the conversion accelerates markedly and the yield increases to 75-80%. The promoting effect of elemental sulfur can be easily explained by the radical-chain mechanism. The reaction starts with one-electron transfer from the nucleophile to the nitro compound further conversions resemble other chain ion-radical substitutions. 

In most cases, the conpling reaction between the radical and nucleophile species is the ratedetermining step in the dark (see, e.g., Tamura et al. 1991, Aznma et al. 1992). This step leads to the formation of RNn-, the prodnct of real substitution. The chain process is completed by a reaction in which one electron is transferred from the product anion-radical to the substrate. A neutral substitution prodnct is formed the propagation loop is closed. 

A mechanism for heteroaromatic nucleophilic substitution which is under considerable active study at the present time is the SRN process, which often competes with the addition-elimination pathway. Srn reactions are radical chain processes, and are usually photochemi-cally promoted. An example is shown in Scheme 22, where (60) is formed by the SrnI pathway and (61) via an initial addition reaction (82JOC1036). 

I. Additions. Radicals can react with anionic species to give radical anion adducts as shown for radical 11. Such addition reactions are steps in chain reaction processes described as SrnI (unimolecular radical nucleophilic substitution) reac-... 

Unactivated aryl halides also undergo nucleophilic displacement via electron transfer in the initial step the so-called SRN1 mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the Srn process often competes with the addition-elimination pathway. The SRN reactions are radical chain processes, and are usually photochemically promoted. For example, ketone (895) is formed by the SRN1 pathway from 2-chloroquinoxaline (894) (82JOC1036). 

This anomeric stabilization of radicals is also observed using halonitrosugars such as 1-C-nitroglycosyl halides [22] 15. Captodative stabilization of the alcoxy nitro radicals explains the radical-chain substitution with mild nucleophiles such as ma-lonate or nitroalkane anions to form 16 (Scheme 8). 

Benzyl cyanide is the product of nucleophilic substitution by cyanide ion on benzyl bromide or benzyl chloride. The benzyl halides are prepared by free-radical halogenation of the toluene side chain. 

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