Reactivity effects electrophilic substitution

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

It has also been stated that the 5-position of selenazoles is more reactive toward electrophilic substitution than that of thiazoles. Such reactivity is still further increased by substituents in the 2-position of the selenazole ring, which can have an —E-effect. Simultaneously, however, an increasing tendency toward ring fission was observed by Haginiwa. Reactions of the selenazole ring are thus limited mainly to the 5-position which, specially in the 2-amino-and the 2-hydrazino-selenazoles, is easily substituted by electrophilic reagents. However, all attempts to synthesize selenazole derivatives by the Gattermann and by the Friedel-Crafts methods... 

Additional acylation studies were also reported (24), (26). In the first case it is claimed that acylation of thiophene is achieved by means of HC104 and acetic anhydride affording a 65 % yield of 2-acetylthiophene. In the second paper Levine and coworkers reported that while 2,5-dimethylthiophene could be readily acetylated, 2,5-dichlorothiophene acetylated sluggishly. This is, however, readily explained, since the presence of chlorine atoms on the thiophene ring decreased its reactivity in electrophilic substitution reactions. In the case of methyl substitution, however, the 3 and 4 positions of the ring are activated toward electrophilic substitution by the inductive and hyperconjugative effects. Thus 2,5-dimethylthiophene was successfully acylated by the boron fluoride etherate method in high yield with three aliphatic anhydrides. 

Phenols are smoothly converted into phenolic aldehydes by reaction with chloroform in the presence of base (the Reimer-Tiemann reaction). This overall formylation reaction is of interest in that it involves the generation from chloroform and alkali of the reactive intermediate, dichlorocarbene (2). This effects electrophilic substitution in the reactive phenolate ions giving the benzylidene dichloride (3) which is hydrolysed by the alkaline medium to the corresponding hydroxyaldehyde. The phenolic aldehyde is isolated from the reaction medium after acidification. 

The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated (see Chapter 5). 

Pyridines are less reactive toward electrophilic substitution than are the corresponding benzenoid compounds because of the electron-withdrawing inductive (-/) and mesomeric (-M) effects of the ring nitrogen. These effects place substantial positive charge on the 2- and 4-carbon atoms (9.14), which are therefore considerably less reactive than the car-... 

These inductive and resonance effects oppose each other. The carbon-halogen bond (shown at left) is strongly polarized, with the carbon atom at the positive end of the dipole. This polarization draws electron density away from the benzene ring, making it less reactive toward electrophilic substitution. 

The reaction apparently proceeds by the electrophilic attack of an acylium ion or protonated mixed anhydride [ArCO(H)OS02CF3], upon the para-position of an aromatic ether (Fig. 37). Loss of a proton results in the formation of 256. The nonsubstituted aryl group of the diphenyl ether was found to be much less reactive toward electrophilic substitution. This group is deactivated by protonation of the keto group in the strongly acidic environment. Therefore, monomers must be designed so that this type of resonance effect does not inhibit substitution at the second site of substitution [Eq. (53)] [162]. 

Take a minute to compare the influence a substituent has on the reactivity of a benzene ring toward electrophilic substitution with its effect on the pK of phenol. Notice that the more strongly deactivating the substituent, the lower the pK of the phenol and the more strongly activating the substituent, the higher the pK of the phenol. In other words, electron withdrawal decreases reactivity toward electrophilic substitution and increases acidity, whereas electron donation increases reactivity toward electrophilic substitution and decreases acidity. 

In quinoline 32, the homocyclic ring A is more reactive towards electrophilic substitution than ring B due to the deactivating effect of the heteroatom hence... 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

The greater reactivity of the 5-position of selenazoles, compared to thiazoles, toward electrophilic substitution has also been demonstrated (19). Substituents in the 2-position possessing a mesomeric donor effect increase the reactivity, but, as Haginiwa (19) observed, also increase the tendancy to ring Opening,... 

A tertiary carbonium ion is more stable than a secondary carbonium ion, which is in turn more stable than a primary carbonium ion. Therefore, the alkylation of ben2ene with isobutylene is much easier than is alkylation with ethylene. The reactivity of substituted aromatics for electrophilic substitution is affected by the inductive and resonance effects of a substituent. An electron-donating group, such as the hydroxyl and methyl groups, activates the alkylation and an electron-withdrawing group, such as chloride, deactivates it. 

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