Reactivity, electrophilic and

The generated quinone methide intermediates, during the disassembly, are highly reactive electrophiles and rapidly react with any available nucleophile (methanol or tetrabutylammonium hydroxide under organic solvent conditions). We could not isolate any significant amount of material that derived from the core molecule, probably due to generation of a mixture of compounds by the addition of different nucleophiles to the quinone methide. This molecule acts as an amplifier of a cleavage... 

Induction of phase II enzymes, which conjugate reactive electrophiles and act as indirect antioxidants, appears to be the means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part,... 

Miller, E.C. and Miller, J.A., "The Metabolism of Chemical Carcinogens to Reactive Electrophiles and Their Possible Mechanisms of Action in Carcinogenesis", Am. Cliem. Soc. Monograph, 1976, 173, 737-762. 

A review of methods of synthesis of aromatic iodo compounds has appeared offering considerable information of potential value to research chemists wishing to prepare iodoheterocycles (84RCR343). Iodination differs from chlorination and bromination in that a much less reactive electrophile (and a much larger one) is involved. The second step of the reaction is usually at least partially rate-determining. Isotope effects are noted in the iodination of indole [68AC(R) 1435], and the transition state resembles the Wheland intermediate more than in chlorination and bromination. 

Miller EC, Miller JA. The metabolism of chemical carcinogens to reactive electrophiles and their possible mechanism of action in carcinogenesis. In Searle CE, ed. Chemical Carcinogens. Washington D.C. American Chemical Society, 1976. A seminal article by the original authors of this important concept. 

This reaction generally requires both a reactive electrophile and a reactive aromatic. For a discussion of it and the pitfalls of not recognizing that it occurs see ref. Id. 

These complexes are very reactive electrophiles, and reactions with alcohols, a thiol, or amines generate new functionally substituted cluster compounds ... 

A review entitled Electrophilic species that can react with benzene are dicationic covers the reactions of benzene with several reactive electrophiles and developments in understanding of the mechanism of the Friedel-Crafts reaction.5... 

If the initial concentration of mercuric bromide is denoted as a, and the concentration of added lithium bromide as c, then a plot of k2 versus c is found7 to be a straight line up to the point at which c = a. After this point, in the region c > a, the linear dependence of k2 on c is still maintained but with an increased slope. This behaviour was interpreted as follows2,7. When c < a, the bromide ion is nearly all taken up to form the species HgBr3 this species is a very reactive electrophile and leads to a transition state (II) of the SE2(cyclic) type, viz. 

Where R4 is a hydrogen or carbon atom, 10.15 is simply an amidine. However, urea 10.16, thiourea 10.17, or guanidine 10.18 and their derivatives may be used. These nucleophiles may be condensed with ester and nitrile functionalities as well as with aldehydes and ketones. Such condensations to afford pyridimidine derivatives are usually facilitated by acid or base catalysis, although certain combinations of reactive electrophilic and nucleophilic compounds require no catalyst at all. Some examples are shown below. 

Cyanoacetylation also involves a more reactive electrophile, and this reaction has been used to examine reactivity patterns in indoles (80CB3675). 

Both again use highly Sn2-reactive electrophiles, and this is the main drawback of enamines. In the next section we consider a complementary class of enol equivalents that react only with highly S l-reactive electrophiles. 

Figure 13. Metabolic activation of an aromatic amine that ultimately can lead to the formation of a reactive electrophile and alkylation of DNA...

Figure 14. Metabolic activation of a dialkylnitrosamine leading to the generation of reactive electrophiles and ultimately to the alkylation of DNA...

That said, enamines are a good solution to the aldehyde enolate problem. Aldehydes form enamines very easily (one of the advantages of the electrophilic aldehyde) and these are immune to attack by nucleophiles—including, most importantly, the enamines themselves. Below are two examples of aldehyde alkylation using the enamine method. Both again use highly SN2-reactive electrophiles, and this is the main limitation of enamines. 

The dialdehyde is a very reactive electrophile, and susceptible to nucleophilic addition at both C4 and C-7. Acetone dicarboxylic acid exists in equilibrium with its enolic tautomer, and is a therefore a good nucleophile at C-3, Dimethylamine is a good nucleophile and base. 

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