Nucleophilic aromatic substitution homolytic

The aryl-thallium bond is thus apparently capable of displacement either by electrophilic or by suitable nucleophilic reagents. Coupled with its propensity for homolytic cleavage (spontaneous in the case of ArTlIj compounds, and otherwise photochemically induced), ArTlXj compounds should be capable of reacting with a wide variety of reagents under a wide variety of conditions. Since the position of initial aromatic thallation can be controlled to a remarkable degree, the above reactions may be only representative of a remarkably versatile route to aromatic substitution reactions in which organothallium compounds play a unique and indispensable role. 

The first paper of the frontier-electron theory pointed out that the electrophilic aromatic substitution in aromatic hydrocarbons should take place at the position of the greatest density of electrons in the highest occupied (HO) molecular orbital (MO). The second paper disclosed that the nucleophilic replacement should occur at the carbon atom where the lowest unoccupied (LU) MO exhibited the maximum density of extension. These particular MO s were called "frontier MO s . In homolytic replacements, both HO and LU.were shown to serve as the frontier MO s. In these papers the "partial" density of 2 pn electron, in the HO (or LU) MO, at a certain carbon atom was simply interpreted by the square of the atomic orbital (AO) coefficient in these particular MO s which were represented by a linear combination (LC) of 2 pn AO s in the frame of the Huckel approximation. These partial densities were named frontier-electron densities . 

Displacements such as this show all the usual characteristics of electrophilic aromatic substitution (substituent effects, etc., see below), but they are normally of much less preparative significance than the examples we have already considered. In face of all the foregoing discussion of polar intermediates it is pertinent to point out that homolytic aromatic substitution reactions, i.e. by radicals, are also known (p. 331) as too is attack by nucleophiles (p. 167). 

Attack on aromatic species can occur with radicals, as well as with the electrophiles (p. 131) and nucleophiles (p. 167) that we have already considered as with these polar species, homolytic aromatic substitution proceeds by an addition/elimination pathway ... 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

Addition of the silyl radical to carbon-carbon double bonds is an elementary reaction of radical hydrosilation (Scheme 1). Homolytic aromatic silationalso occurs involving silyl radicals. Silyl radicals are nucleophilic owing to the high SOMO energy, as evidenced by the directive effects in the hemolytic aromatic substitution. The intermediate cyclohexadienyl radicals have been observed by ESR. 

Radical cyclizations of nucleophilic N-alkyl radicals 96 onto the benzimidazole 2-position, mediated by tributyltin hydride and activated by quater-nizing the pyridine-like N-3 of imidazole with camphorsulfonic acid, have recently been reported (Scheme 20) [67]. These new five-, six- and seven-membered homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred upon the use of large excesses of the azo-initiator, l,T-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. The intermediate 97 aromatizes in high yields to the cy-clized benzimidazoles 98. 

The reaction of a nucleophilic alkyl radical R with benzene affords the a-complex 1, a fairly stable cyclohexadienyl radical, which under oxidizing conditions leads to cation 2 (Scheme 1). Depending on the stability of the attacking radical, the formation of 1 is a reversible process. Deprotonation eventually affords the homolytic aromatic substitution product 3. If the reaction is performed under non-oxidizing conditions, cyclohexadienyl radical 1 can dimerize (—> 4), disproportionate to form cyclohexadiene 5 and the arene 3, or further react by other pathways [3]. 

These reactivity trends clearly show that polar effects are involved in these radical substitution reactions. The transition state is thought to include a charge transfer 9) from the radical (electron donor) to the pyridinium ion (electron acceptor) [13], Frontier Molecular Orbital Theory (FMO) [14] has been applied to explain the reactivity differences which have been observed upon varying the substituents at the pyridinium ion and upon altering the nucleophilicity of the attacking radical. Moreover, FMO can be used to explain the regioselectivities obtained in these homolytic aromatic substitutions. The LUMO of the substituted pyridinium cation... 

Compared to the intramolecular aromatic alkylation with nucleophilic radicals, the analogous process with electrophilic radicals is far less common. Citterio carefully studied the Mn(OAc)3-mediated intramolecular homolytic aromatic substitution of various dialkyl malonates [71, 73]. He showed that the reaction is well suited for the formation of 5- (see 45), 6- (see 46) and 7-membered benzanellated rings (see 47). For cyclizations forming a 6-membered ring, high yields were obtained in the alkylation of electron-rich as well as electron-poor arenes. However, the formation of the 7-membered ring occurred only with electron-rich arenes. Cerium(IV) ammo-... 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

Exactly how the stabilized aromatic cation radical is converted into the nuclear chlorinated product, is not at present fully understood. As represented in eqn (135), nucleophilic substitution could arise from initial capture of the aromatic cation radical by chloride ion involving appropriate substituted cyclohexadienyl-type radicals ( ArHCl), in which case the substitution pattern (at least the ortho/para ratio of products) might be expected to resemble more those from typical homolytic aromatic substitution processes rather than those from electrophilic substitutions, as observed experimentally. At present, there is a scarcity of significant mechanistic information relating to nucleophilic capture of aromatic cation radicals, although in every reported case [vide infra) the position of substitution corresponds with that arising from comparable electrophilic processes. 

Radical substitution reactions and their mechanisms and applications have been reviewed several times [189,190]. Thiophene participates well in radical reactions. There are reviews describing both unimolecular radical nucleophilic substitutions (SrnI) [191] and homolytic aromatic substitutions (HAS) of thiophenes [192]. The formation of thiophene radicals from peroxides, thienylamines and iodothiophenes has been discussed [192]. 

The first examples of selective substitution of heteroaromatic bases by carbon-centered radicals were reported by Minisci and his group at the end of the 1960s (Scheme 1) [1,2]. Those manuscripts, which can be considered the first accounts of the so-called "Minisci reaction" [3], played a decisive role to the chemical community in reconsidering the potentiality of free-radical aromatic substitutions. In fact, until then the homolytic process had been considered of poor interest compared with the electrophilic and nucleophilic ionic substitutions, due to the discouraging results achieved witii homolytic arylation, the reaction most studied so far [4]. The low selectivity observed for that reaction was erroneously assumed as a general feature of homolytic aromatic substitution and this misinterpretation was overcome only when it was recognized that the polar effect could play a key role in free-radical reactions as well. 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

In Volume 13 reactions of aromatic compounds, excluding homolytic processes due to attack of atoms and radicals (treated in a later volume), are covered. The first chapter on electrophilic substitution (nitration, sulphonation, halogenation, hydrogen exchange, etc.) constitutes the bulk of the text, and in the other two chapters nucleophilic substitution and rearrangement reactions are considered. 

Some other aromatics azidated in this way included 1,2,3-trimethoxybenzene (at C-5), naphthalene (at C-l), mesitylene, etc. Mechanistic studies have shown that azide reacts as a nucleophile with aryl cation radicals formed through electron abstraction by BTI. With p-alkylanisoles bearing at least one benzylic proton, BTI and Me3SiN3 in acetonitrile gave sp3-C-substitution products, homolytically. Among the R groups were not only alkyls but also cyano, nitro and others [102]. 

---