Substitution by the SrnI Mechanism

R. A. Rossi and R. H. de Rossi, Aromatic Substitution by the SrnI Mechanism , American Chemical Society, Washington, DC, 1983. 

Rossi, R. A. Pierini, A. B. Palacios, S. M. Nucleophilic substitution by the SrnI mechanism on alkyl halides. Adv. Free Radical Chem. 1990, 3, 193-252. 

Instances of substitution of hindered alkyl halides by the SrnI mechanism have also been documented. Some examples are shown below. 

The second part, substitution of N2 by I, proceeds by the SrnI mechanism. 

Electron transfer is also the first step of the SrnI substitution mechanism (Chapter 2). In reactions that proceed by the SrnI mechanism, the electron donor is usually the nucleophile. The nucleophile may be photoexcited to give its electron more energy and make it more prone to transfer. 

In the thianthrene series, o-diodo- and o-bromochloro derivatives react under photostimulation by the SrnI mechanism with 3,4-toluenedithiolate anion to give good yields of the cyclic substituted compound, 2-methylthianthrene <87JOC1089>. 

Substitution by the Sn2 mechanism and jS-elimination by the E2 and Elcb mechanisms are not the only reactions that can occur at C(sp )— X. Substitution can also occur at C(sp )—X by the SrnI mechanism, the elimination-addition mechanism, and metal insertion and halogen-metal exchange reactions. Alkyl halides can also undergo a-elimination reactions to give carbenes. 

Vinylic halides can react by a SrnI mechanism (p. 855) in some cases. An example is the FeCl2 catalyzed reaction of l-bromo-2-phenylethene and the enolate anion of pinacolone (t-BuCOCH2 ), which gave a low yield of substitution products along with alkynes. ... 

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." ... 

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). 

A more intriguing type of competition is due to radical processes, which usually involve the substrate radical anion. These can fragment, if they carry a suitable substituent, via anion expulsion.56 The resulting aryl radical, Ar, can form the reduced product, ArH, by hydrogen abstraction57 or the product of substitution via reaction with the nucleophile according to the SrnI mechanism, discussed in Chapter 2.2 of this volume. Examples of competition between SnAt and radical processes of this type have been reported.57-59... 

However, the competition between Srn 1 and polar abstraction mechanisms is complicated in certain reactions by the formation of disulfides which is inhibited by radical and radical anion traps, and requires photolysis [23, 24]. These results implicate a third possibility, the chain SET redox mechanism (Srt2, i.e. substitution, electron transfer, bimolecular), Scheme 10.34. This alternative mechanism occurs when the intermediate radical anion can be intercepted by the thiolate (Equation 10.23) prior to the dissociation required in the SrnI mechanism (Equation 10.17 in Scheme 10.29). It becomes possible when either... 

Solvation of thiolates is similarly low in both protic and dipolar aprotic solvents because of the size and polarisability of the large weakly basic sulfur atom, so is unlikely to contribute appreciably to the observed solvent effect. The intermediate nitro radical anion is stabilised by H-bonding in a manner which retards its dissociation in the SrnI mechanism (upper equation in Scheme 10.35). In contrast, the electron flow in the direct substitution at X (lower equation in Scheme 10.35) is such that solvation by methanol promotes the departure of the nucleofuge. In summary, protic solvation lowers the rate of the radical/radical anion reactions, but increases the rate of the polar abstraction yielding disulfide. 

A practical access to 2-biphenyl alcohols 95 has been discovered by Petrillo (Scheme 36) [152]. Azo sulfides 96, which are employed as masked diazonium salts, do not undergo azo coupling reactions. In combination with 4-substituted phenolates 97, photochemically initiated arylations can even be conducted as chain processes according to the SrnI mechanism. Given their high reductive potential, the cyclohexadienyl intermediates 98 are able to rearomatize by a single electron... 

Unactivated aryl halides will undergo nucleophilic displacement via electron transfer in the initial step the so-called SrnI mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the SRN process often competes with the additionelimination pathway. SRN reactions are radical chain processes and are usually photochemically promoted. For example, ketone 913 is formed by the SRN1 pathway from 2-chloroquinoxaline 912. 

Alternatively, the SrnI mechanism can be coupled to nucleophilic additions as was the case during the formation of substituted indole 212 [182], an interesting variation on a reaction first reported by Beugelmans and Roussi [183]. 

The best nucleophiles for the SrnI mechanism can make a relatively stable radical in the initiation part, either by resonance (enolates) or by placing the radical on a heavy element (second-row main-group or heavier nucleophiles). The best electrophiles are aryl bromides and iodides. If light is required for substitution to occur, the mechanism is almost certainly SrnI. Substitution at alkenyl C(sp2)-X bonds can also occur by an SrnI mechanism. 

In summary, aryl halides can undergo substitution by addition-elimination, SrnI, or elimination-addition mechanisms under basic conditions. The addition-elimination mechanism is most reasonable when the arene is electron-poor. When the arene is not electron-poor, the SrnI mechanism is most reasonable either when the nucleophile is a heavy atom or is delocalized, when light is required, or when a catalytic amount of a one-electron reducing agent is required. The elimination-addition mechanism is most reasonable when the arene is not electron-poor and when very strong base (pk b > 35) is used. 

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