Substitution, Radical, Nucleophilic

Some Sn2 reactions have electron transfer characteristics. Such single-electron transfer (SET) reactions start with an electron transfer from the nucleophile to the electrophile. 

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A large number of radical reactions proceed by redox mechanisms. These all require electron transfer (ET), often termed single electron transfer (SET), between two species and electrochemical methods are very useful to determine details of the reactions (see Chapter 6). We shall consider two examples here - reduction with samarium di-iodide (Sml2) and SRN1 (substitution, radical-nucleophilic, unimolecular) reactions. The SET steps can proceed by inner-sphere or outer-sphere mechanisms as defined in Marcus theory [19,20]. 

Substitutions by the SRn 1 mechanism (substitution, radical-nucleophilic, unimolecular) are a well-studied group of reactions which involve SET steps and radical anion intermediates (see Scheme 10.4). They have been elucidated for a range of precursors which include aryl, vinyl and bridgehead halides (i.e. halides which cannot undergo SN1 or SN2 mechanisms), and substituted nitro compounds. Studies of aryl halide reactions are discussed in Chapter 2. The methods used to determine the mechanisms of these reactions include inhibition and trapping studies, ESR spectroscopy, variation of the functional group and nucleophile reactivity coupled with product analysis, and the effect of solvent. We exemplify SRN1 mechanistic studies with the reactions of o -substituted nitroalkanes (Scheme 10.29) [23,24]. 

SrnI reactions (substitution-radical nucleophilic) are light-catalysed reactions of synthetic utility. Many of the reactions are detailed in a recent review (Bunnett, 1978). The extent to which these reactions are photo-initiated chain reactions is not known. In the reaction of diethyl phosphite anion the first... 

SrnI Process (Substitution, Radical-Nucleophile, Unimolecular)... 

The displacement of bromine, in the relative order 2 > 3 > 4, by an enolate or related anion under irradation, known as an SrnI process (Substitution Radical Nucleophilic, unimolecular), involves photostimulated transfer of an electron from the enolate to the heterocycle, loss of bromide to generate a pyridyl radical which then combines with a second mol of enolate, generating the radical anion of product, transfer of an electron from which sustains the chain process.The equivalent photo-catalysed displacement of bromide by hydroxide gives 3-hydroxypyridine. ... 

This chain reaction is analogous to radical chain mechanisms for nucleophilic aliphatic nucleophilic substitution that had been suggested independently by Russell and by Komblum and their co-workers. The descriptive title SrnI (substitution radical-nucleophilic unimolecular) was suggested for this reaction by analogy to the SnI mechanism for aliphatic substitution. The lUPAC notation for the SrkjI reaction is (T -t- Dm -t- An), in which the symbol T refers to an electron transfer. When the reaction was carried out in Ihe presence of solvated electrons formed by adding potassium metal to the ammonia solution, virtually no aryne (rearranged) products were observed. Instead, reaction of 95c produced only 98 (40%) and 94 (40%) but no 99, and reaction of 96c produced 99 (54%) and 94 (30%) with only a trace of 98. ... 

In 1970, Bunnett and Kim reported a new nucleophilic aromatic substimtion reaction the S l mechanism (substitution, radical-nucleophilic, first order) [77-80]. Nine years later, Bunnett [81] and Beugelmans [82,83] independently discovered the application of the S l reaction to the synthesis of indoles (Scheme 10). In Bunnett s work (equation 1) the aeetone enolate (and others) was generated from acetone and potassium tert-butoxide (tert-butyl alcohol) in the presence of potassium amide in liquid ammonia [81]. Indoles 16 to 18 were also prepared by Bard and Bunnett. Beugelmans and Roussi employed a similar... 

Besides nucleophilic and electrophilic pathways for aromatic substitutions, there are also radical pathways. With aromatic rings that are easily reduced, this is a common mechanism, because the benzene ring can delocalize the radical anion. The radical chain mechanism is referred to as SrnI, (substitution, radical-nucleophilic, unimolecular). An example is shown in Eq. 10.118. 

There is still another substitution mechanism to consider, although it is much less common. It is called SrnI (substitution, radical, nucleophilic, unimolecular) and involves a radical chain mechanism, unlike the SET mechanism just described. We have seen a radical chain substitution mechanism in Chapter 10 when we considered radical aromatic substitution (Section 10.22). 

SrnI (substitution, radical, nucleophilic, unimolecular). Section 11.6... 

Photo-induced aromatic substitution reactions occur through an electron transfer process, which creates an aromatic radical anion or aromatic radical cation as intermediate. This intermediate couples with the electrophile or nucleophile radical to give the product. This mechanism is called Sr I (where the abbreviations stand for substitution, radical, nucleophilic, and first order). Photoirradiation of aromatic compounds in the presence of nucleophiles gives nucleophilic-substituted products different from those of thermal reaction. For example, 3,4-dimethoxynitrobenzene on UV irradiation in presence of hydroxide ion gives 3-hydroxy-substituted product, while on heating gives 4-hydroxy-substituted product [57]. 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

Formation of metastable p-peroxo complexes (also adduct formation, nucleophilic substitution, radical coupling, etc.)... 

The yields of reaction products from thermal nucleophilic substitution reactions in DMSO of 0- and p-nitrohalobenzenes (Zhang et al. 1993) or p-dinitrobenzene (Liu et al. 2002) with the sodium salt of ethyl a-cyanoacetate were found to be markedly diminished from the addition of small amounts of strong electron acceptors such as nitrobenzenes. At the same time, little or no diminution effects on the yields of the reaction products were observed from the addition of radical traps such as nitroxyls. These results are consistent with the conclusion that such reactions proceed via a nonchain radical nucleophilic substitution mechanism (Scheme 4.26). 

Thus the overall picture of homolytic substitution of heteroaromatic compounds has undergone only minor modification as regards arylation, but very great modification as regards substitution with nucleophilic radicals, since Norman and Radda reviewed the field in these Advances. 

At the same time, delocalization of unpaired spin in the free-radical product appears to be important for the course of the substitution reaction. For example hydrogen shift in sabinene radical cation 39a leads to a conjugated system (40 ) nucleophilic attack on l-aryl-2-alkylcyclopropane radical cations 43 or 47 produces benzylic radicals nucleophilic attack on 39a generates an allylic species and attack on the tricyclane radical cations 55 or 56 forms tertiary radicals. Apparently, formation of delocalized or otherwise stabilized free radicals is preferred. 

Many synthetically important substitutions of aromatic compounds are effected by nucleophilic reagents. There are several general mechanisms for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, metal-catalyzed, and radical or electron-transfer processes. (See Sections 10.5, 10.6, 12.8, and 12.9, Part A to review these mechanisms.)... 

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-... 

The lack of reactivity of 3-halo substituents under non-radical nucleophilic substitution conditions allows differential functionalization of pyri-dines by 3-umpolung and 2-nucIeophilic substitution processes. Thus, treatment of 2-fluoro-3-iodopyridine (189) with oxygen or amine nucleophiles affords products 191 which, upon subjection of SRN1 reactions with carbon, phosphorus, and sulfur systems, give 2,3-difunctionalized pyri-dines 192 (Scheme 56) (88JOC2740). 

Most synthetically useful radical addition reactions pair nucleophilic radicals with electron poor alkenes. In this pairing, the most important FMO interaction is that of the SOMO of the radical with the LUMO of the alkene.36 Thus, many radicals are nucleophilic (despite being electron deficient) because they have relatively high-lying SOMOs. Several important classes of nucleophilic radicals are shown in Scheme IS. These include heteroatom-substituted radicals, vinyl, aryl and acyl radicals, and most importantly, alkyl radicals. 

There are several examples of the addition reactions of caibonyl-substituted radicals to alkenes by the tin hydride method. The first reaction cited in Scheme 32 is a clear-cut example of reversed electronic requirement an electrophilic radical pairing with a nucleophilic alkene.60 Because enol ethers are not easily hydrostannylated, the use of a chloride precursor (which is activated by the esters) is possible. Indeed, the use of a bromomalonate results in a completely different product (Section 4.1.6.1.4). The second example is more intriguing (especially in light of die recent proposals on the existence of ambiphilic radicals) because it appears to go against conventional wisdom in the pairing of radicals and acceptors.118,119... 

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