Electrophilic/Nucleophilic Aromatic Substitution (Chapter 16 +22)

• The para– and orth– positions become more positively charged. • The negativity of the meta– position is unaffected. Since the meta– position is more negatively charged relative to the para–/ortho– positions, EAS reactions with EWD-substituted benzes are meta-directing.

Meta-Directing Since the benzene ring is more electron-deficient, it will participate in EAS reactions at a slower rate.

• The para– and orth– positions become more negatively charged. • The negativity of the meta– position is unaffected. Since the meta– position is more negatively charged relative to the para–/ortho– positions, EAS reactions with EWD-substituted benzes are meta-directing.

Para–Directing + Ortho–Directing Since the benzene ring is more electron-dense, it will participate in EAS reactions at a faster rate.

• —X • —R • —OR • —OCOR • —OH • —NHCOR • —NR2 • —NHR • —NH2

• —COOH • —COOR • —COR • —CF3 • —CN • —SO3+H • —NO2 • —NR3+

Since an EDG-substituted benzene is more reactive than typical benzene, EAS of a halogen to an EDG-substituted benzene proceeds to the tri-halogenated product. Monosubstitution of the EDG-substituted benzene can only occur via the use of protecting groups to the ortho-/para- positions.

• Strong EDG-substituted benzenes do not require an acid catalyst for EAS reactions to occur. • Weak EDG-substituted benzenes REQUIRE an acid catalyst for EAS reactions to occcur. • Strong electron-donating groups (e.g. alkoxy groups) contribute electronegativity via resonance. • Weak electron-donating groups (e.g. alkyl groups) contribute electronegativity via hyperconjugation.

Substitution at the para-position is favored (over substitution at the ortho-position) due to steric repulsion/effects at the ortho-position. All electron-donating groups (EXCEPT alcohol groups and amino groups and methyl groups) sterically hinder EAS at the ortho-position, yet larger groups will have a greater steric effect.

Due to being highly electronegative, halogen atoms exhibit a strong inductive withdrawal force and possess relatively unpolarizable lone-pair π electrons. The inductive withdrawal force is stronger than the electron-donating resonance effect, so the halogen is weakly electron-withdrawing. Halogen-substituents weakly deactivate the benzene ring, yet they are ortho-directing and para-directing.

• The reactivity is controlled by the electron-withdrawing effects of the halogen. • The regioselectivity is controlled by the electron-donating resonance effect of the halogen.

Nitrogen has a lower electronegativity than Oxygen, so its lone-pair electrons exhibit are better able to delocalize.

• —OH • —NH2 • —CH3 • —OCH3 • —CH2CH3 • —CO2H • Substituents that are larger than these groups will greatly restrict EAS at the ortho-position. • EAS at a position ortho to any two substituents will always be sterically restricted.

The electronic effects of individual substituents are additive. E.g. Two electron-withdrawing groups will express a greater overall deactivating effect on the benzene than any single electron-withdrawing group.

The strongest activator (i.e. strongest electron-donating group) determines the electropilic substitution pattern to the benzene. A weakly electron-donating groups will be a stronger activator than a stongly electron-withdrawing group.

Reduction of Nitro Group Nitro = —NO2

Reduction of Acyl Group Acyl = —COR

Williamson Ether Synthesis w/ Phenol

Acetylation of Amino Group Acetyl = CH3—CO—Cl

• Grignard Reagent • Organolithium Reagent

The conversion of the alcohol group to an alkoxy group directs EAS monofunctionalization primarily to the para– position. —OH → —OR The alkoxy group causes para–position functionalization to be favored due to the steric effects/repulsion on the ortho–positions.

The conversion of the amino group to an amide group directs EAS monofunctionalization primarily to the para– position. —NH2 → —NHCOR The amide group causes para–position functionalization to be favored due to the steric effects/repulsion on the ortho–positions.

EAS reactions will proceed until the tri-substituted product is formed, unless the strongly activating substituent imparts steric effects. If the strong EDG substituent imparts steric effects, monofunctionalization at the para–position will be highly favored.

Beneze compounds with strongly deactivating substituents will not undergo Friedel-Craft Acylation (due to the relatively low reactivity/electrophilicity of the acylium intermediate). • Strongly deactivating substituents include all resonance electron-withdrawing groups (and CF3). • Unreactive Aryl compounds will undergo EAS reactions with all cationic electrophiles.