Electron-withdrawing group substituent

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

The electronic influence of the 4-substituent corresponds to a relative increase in the kinetic acidity of the C-5 proton when an electron-withdrawing group (R=Ph) is situated at the 4-position and to a relative increase in the kinetic acidity of the 2-methyl group when an electron-donating group (R = Me) is at the same position (Table 1-59). 

This makes the nitro group a powerful electron withdrawing deactivating substituent and a meta director... 

Electron releasing substituents attached to the ring have a negligible effect on the acidity of phenols Strongly electron withdrawing groups increase the acidity The compound 4 nitro 3 (tnfluoromethyl)phenol for example is 10 000 times more acidic than phenol... 

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. 

Pyrrole is soluble in alcohol, benzene, and diethyl ether, but is only sparingly soluble in water and in aqueous alkaUes. It dissolves with decomposition in dilute acids. Pyrroles with substituents in the -position are usually less soluble in polar solvents than the corresponding a-substituted pyrroles. Pyrroles that have no substituent on nitrogen readily lose a proton to form the resonance-stabilized pyrrolyl anion, and alkaU metals react with it in hquid ammonia to form salts. However, pyrrole pK = ca 17.5) is a weaker acid than methanol (11). The acidity of the pyrrole hydrogen is gready increased by electron-withdrawing groups, eg, the pK of 2,5-dinitropyrrole [32602-96-3] is 3.6 (12,13). 

This method is suitable only for the preparation of 4-substituted and/or 3,4-disubstituted derivatives, the substituents being only alkyl, aryl or heteroaryl groups. The presence of electron-withdrawing groups in the unsaturated side chain prevents the cyclization step. This is understandable if the influence of such groups on the stability of the intermediate carbonium ion is considered. Of more limited application is the analogous cyclization of diazotized o-aminophenylpropiolic acids, the reaction being referred to as the Richter synthesis (Scheme 70). A related synthesis (also referred to as the Neber-Bossel synthesis)... 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

The pATr+ values allow for a comparison of the stability of carbocations. The carbocations that can be studied in this way are all relatively stable carbocations. The data in Table 5.1 reveal that electron-releasing substituents on the aryl rings stabilize the carbocation (more positive pA r+) whereas electron-withdrawing groups such as nitro are destabilizing. This is what would be expected from the electron-deficient nature of the carbocation. 

The effect of the bond dipole associated with electron-withdrawing groups can also be expressed in terms of its interaction with the cationic u-complex. The atoms with the highest coefficients in the LUMO 3 are the most positive. The unfavorable interaction of the bond dipole will therefore be greatest at these positions. This effect operates with substituents such as carbonyl, cyano, and nitro groups. With ether and amino substituents, the unfavorable dipole interaction is overwhelmed by the stabilizing effect of the lone-pair electrons stabilizing 3. 

Radical chlorination reactions show a substantial polar effect. Positions substituted by electron-withdrawing groups are relatively unreactive toward chlorination, even though the substituents may be potentially capable of stabilizing the free-radical intermediate " ... 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

The replacement of a substituent on an aromauc nng by a nucleophile is termed arylaUon. This chapter considers the replacement by nucleophihc oxygen, sulfur, nitrogen, and carbon of aromatic fluonne atoms, which are often activated by electron-withdrawing groups. 

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