Substitution, electrophilic groups

The mechanism of substitution on an electron-rich benzene ring is electrophilic substitution, electrophilic attack on an atom and the replacement of one atom by another or by a group of atoms. The fact that substitution occurs rather than addition to the double bonds can be traced to the stability of the delocalized 7T-electrons in the ring. Delocalization gives the electrons such low energy—that is, they are bound so tightly—that they are unavailable for forming new cr-bonds (see Sections 2.7 and 3.12). 

G. Forat, J.-M. Mas, L. Saint-Jalmes (Rhone-Poulenc Chimie). Method for Grafting a Substituted Difluoromethyl Group to a Compound Containing an Electrophilic Group with Microwave Irradiation. PCT International Application WO 5, 609,1998 (FR Application 96/ 9,754, 1 Aug 1996) Chem. Abstr. 1998, 128, 166999u. 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

The formation of six-membered or larger rings by intramolecular C-H bond insertion normally requires the attacked position to be especially activated towards electrophilic attack [1157,1158]. Electron-rich arenes or heteroarenes [1159-1162] and donor-substituted methylene groups can react intramolecularly with electrophilic carbene complexes to yield six- or seven-membered rings. Representative examples are given in Table 4.8. 

Analogous reactions of electron-rich aromatic compounds can be found in the literature When 4-substituted-N.N-dimethylanilines 231 are treated with dia-zonium salts or some other electrophiles, position 4 is substituted by the electrophile group to 4-substituted dimethylanilines ... 

Several 1,1-disubstituted olefins with electrophilic groups react with alcohols to undergo addition reactions, and with alkoxide ions to undergo substitution reactions to afford ortho esters [120a-c, 125a, b, 130-137] (Eq. 37). 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

Removal of the 0-substituted Fp group can be achieved by conversion into the cationic alkene-Fp complex using Ph3CPF6 and subsequent treatment with iodide, bromide or acetonitrile. Oxidative cleavage with ceric ammonium nitrate in methanol provides the methyl esters via carbon monoxide insertion followed by demetallation. The [3 + 2]-cydoaddition has been successfully applied to the synthesis of hydroazulenes (Scheme 1.11) [34]. This remarkable reaction takes advantage of the specific nucleophilic and electrophilic properties of V-allyl-, cationic t 5-dienyl-, cationic ri2-alkene- and ti4-diene-iron complexes, respectively. 

For electrophiles such as Me3SiCH2X strong ground-state destabilization has been observed for X = 4-nitrobenzoate[130]. For X= halide, on the other hand, this ground-state destabilization is significantly smaller, and it may therefore be advisable to choose carboxylates or sulfonates as leaving groups when alkylations with a-silyl-substituted electrophiles are to be performed. 

Nitro groups are ring-deactivating. Thus, as we substitute nitro groups for hydrogens, we make the ring less and less reactive toward further electrophilic substitution and, therefore, we must increase the severity of the reaction conditions. 

The splitting is facilitated, when the disilane is substituted by some electrophilic groups. Symmetric disilanes have a greater activation energy and entropy change in the reaction than do asymmetric substituted disilanes. 

For the synthesis of orfbo-bromotoluene we use a sulphonic acid. o-Bromotoluene could be synthesised by bromination of toluene or by Friedel-Crafts alkylation of bromobenzene (Fig. T). However, the reaction would also give the para substitution product and this is more likely if the electrophile is hindered from approaching the ortho position by unfavourable steric interactions. Alternatively we can substitute a group at the para position before carrying out the bromination. 

Annelation. The Pd(0) complex in combination with N(C2H5)3 (1.5-2 equiv.) effects cyclic carbopalladation of substrates such as 1, a cyclohexene substituted by a y-iodoallyl electrophile group and activated by a carbonyl group,... 

Typically, electron density of different carbon atoms in the benzene core is judged from the amount of isomers (%) which form on electrophilic substitution of hydrogen in the benzene core for an electrophilic group, such as nitroxyl in the mononitration. 

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