Aromatic substitution reactions combining

During my early years as an assistant professor at the University of Kentucky, I demonstrated the synthesis of a simple quinone methide as the product of the nucleophilic aromatic substitution reaction of water at a highly destabilized 4-methoxybenzyl carbocation. I was struck by the notion that the distinctive chemical reactivity of quinone methides is related to the striking combination of neutral nonaromatic and zwitterionic aromatic valence bond resonance structures that contribute to their hybrid resonance structures. This served as the starting point for the interpretation of the results of our studies on nucleophile addition to quinone methides. At the same time, many other talented chemists have worked to develop methods for the generation of quinone methides and applications for these compounds in organic syntheses and chemical biology. The chapter coauthored with Maria Toteva presents an overview of this work. 

In some cases the nucleophilic capture of a radical cation is followed by coupling with the radical anion (or possibly with the neutral acceptor), resulting ultimately in an aromatic substitution reaction. Thus, irradiation of 1,4-dicyanobenzene in acetonitrile-methanol (3 1) solution containing 2,3-dimethylbutene or several other olefins leads to capture of the olefin radical cation by methanol, followed by coupling of the resulting radical with the sensitizer radical anion. Loss of cyanide ion completes the net substitution reaction [144]. This photochemical nucleophile olefin combination, aromatic substitution (photo-NOCAS) reaction has shown synthetic utility (in spite of its awkward acronym). 

Step 1 Polystyrene and the phthalimide combine in an electrophilic aromatic substitution reaction... 

The orientation of aromatic substitution reactions and chemical reactivities in general actually do not measure the effect of resonance alone upon a resting system but rather the combined operation of resonance and the polarizability of double bonds or conjugated systems (p. 28). For many reactions it is not necessary to consider each separately since polarizability simply intensifies the contribution of certain resonance structures. (For example, see p. 156.)... 

One way of carrying out nucleophilic aromatic substitution reactions under mild conditions is the Ar RNl process, which is initiated by (usually, but not necessarily, photoinduced) electron transfer to an aryl halide, e.g., from an enolate Cleavage of the resulting aryl radical anion with loss of a halide anion gives an aryl radical that combines with the enolate, thus forming the desired aryl-carbon bond. 

Mangion, D., Arnold, D. R., Photochemical Nucleophile Olefin Combination, Aromatic Substitution Reaction. Its Synthetic Development and Mechanistic Exploration, Acc. Chem. Res. 2002, 35, 297 304. 

These reactions are very useful in synthesis problems. You will find that some problems will combine these reactions with electrophilic aromatic substitution reactions. These problems can range in difficulty, and they can get really tough at times. You will find many, many such problems in your textbook. As you go through some of the challenging problems in your textbook, I will leave you with a bit of last-minute advice ... 

The PET reactions of isobutylene(2-methylpropene) (21) in the absence of methanol have yielded a novel photochemical nucleophile-alkene combination aromatic substitution reaction. The solvent, acetonitrile, was found to act as a nucleophile and add to the alkene radical cation to give a distonic radical cation that subsequently adds to the 1,4-dicyanobenzene radical anion. Cyclization to the ortho position of the phenyl group leads to product formation. Two-colour, two-laser techniques have been used to study the photolysis of a, a -dichloro-o- or -p-xylene to yield xylylenes. ... 

Nucleophilic aromatic substitution reactions have been examined in terms of a model based on the combination of a cation with an anion. The reactivities of 2,4-dinitro-halogenobenzenes with nucleophiles have been shown to be related to the basicity and polarisability of the nucleophile and the polarisability of the substrate only atoms and bonds at or near the reaction centre are involved in producing the polarisability effects. Hammett cr values have been measured for unsaturated groups —CH=NX in the 4-position for nucleophilic displacement of chlorine in 2-nitrochlorobenzene derivatives and compared with those for established activating groups. ... 

Arnold, D.R. and Snow, M.S., The photochemical nucleophile-olefin combination, aromatic substitution reaction. Part 2. Cyclic olefins, methanol, 1,4-dicyanobenzene, Can. J. Chem., 66, 3012, 1988. 

Mangion, D. and Arnold, D.R., Photochemical nucleophile-olefin combination, aromatic substitution reaction. Its synthetic development and mechanistic exploration, Acc. Chem. Res., 35, 297, 2002. 

Grant et a/.397 examined the reactions of hydroxy radicals with a range of vinyl and a-methylvinyl monomers in organic media. Hydroxy radicals on reaction with AMS give significant yields of products from head addition, abstraction and aromatic substitution (Table 3.8) even though resonance and steric factors combine to favor "normal tail addition. However, it is notable that the extents of abstraction (with AMS and MMA) arc less than obtained with t-butoxy radicals and the amounts of head addition (with MMA and S) are no greater than those seen with benzoyloxy radicals under similar conditions. It is clear that there is no direct correlation between reaclion rale and low specificity. 

In Section 8.2.3.2, we discussed arylation of enolates and enolate equivalents using palladium catalysts. Related palladium-phosphine combinations are very effective catalysts for aromatic nucleophilic substitution reactions. For example, conversion of aryl iodides to nitriles can be done under mild conditions with Pd(PPh3)4 as a catalyst. 

A combination of 2,3 sigmatropic rearrangement (Pummerer-type reaction) followed by an electrophilic aromatic substitution of the intermediate sulfenium ion, the formation of an iminium ion and, finally, a second electrophilic aromatic substitution, was used by Daich and coworkers for the synthesis of iso-indolo-isoquinolinones as 4-314 (Scheme 4.68) [106]. Thus, reaction of the two diastereo-meric sulfoxides 4-313, easily obtainable from 4-312 by a Grignard reaction and oxidation, led to 4-314 as a single product after crystallization in 42% yield. 

As previously discussed, activation of the iridium-phosphoramidite catalyst before addition of the reagents allows less basic nitrogen nucleophiles to be used in iridium-catalyzed allylic substitution reactions [70, 88]. Arylamines, which do not react with allylic carbonates in the presence of the combination of LI and [Ir(COD)Cl]2 as catalyst, form allylic amination products in excellent yields and selectivities when catalyzed by complex la generated in sim (Scheme 15). The scope of the reactions of aromatic amines is broad. Electron-rich and electron-neutral aromatic amines react with allylic carbonates to form allylic amines in high yields and excellent regio- and enantioselectivities as do hindered orlAo-substituted aromatic amines. Electron-poor aromatic amines require higher catalyst loadings, and the products from reactions of these substrates are formed with lower yields and selectivities. 

It should be emphasized that the wide scope of nucleophilic aromatic photosubstitution does not imply that it will work indiscriminately with any combination of aromatic compound and nucleophile. On the contrary, there are pronounced selectivities. The general picture now arising shows a field with certainly as much variability and diversification as chemists, in the course of growing experience, have learned to appreciate in the area of classical (thermal) aromatic substitution. It is one of the aims of this article to contribute to a description and understanding of the various reaction paths and mechanisms of nucleophilic aromatic photosubstitution, hopefully to the extent that valuable predictions on the outcome of the reaction in novel systems will become feasible. 

The photochemical nucleophile-olefin combination aromatic substitution (photo-NOCAS) reaction received considerable attention from many groups not only because of its synthetic value because the yields of nucleophile-olefm-arene (1 1 1) adducts can be high but also because of interesting mechanistic details (Scheme 48). 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Substitution of halopurines at C-2 and C-6 has become a well-developed synthetic process, with a wide variety of nucleophilic aromatic substitution and palladium-catalyzed C-N or C-O hond formations exemplified in the literature. The use of selective, sequential substitution reactions on polyhalopurine scaffolds is the basis of an increasing number of combinatorial syntheses of polysubstituted purines, both in solution and on solid phase. The introduction of N-, 0-, or S-substituents has often been combined with transition metal-catalyzed C-C bond-forming reactions (see Section 10.11.7.4.2) and selective N-alkylation (see Section 10.11.5.2.1) to provide versatile routes to purines with multiple, diverse substituents. 

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