Electrophilic/Nucleophilic Aromatic Substitution (Chapter 16 +22) Flashcards
Effect of EWD on Benzene EAS
EWD = Electron-Withdrawing Groups
- 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.
Electron-Withdrawing Group
Electrophilic Aromatic Substitution
Meta-Directing
Since the benzene ring is more electron-deficient, it will participate in EAS reactions at a slower rate.
Effect of EDG on Benzene EAS
EDG = Electron-Donating
- 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.
Electron-Donating Group
Electrophilic Aromatic Substitution
Para–Directing + Ortho–Directing
Since the benzene ring is more electron-dense, it will participate in EAS reactions at a faster rate.
Ortho-Directing Groups + Para-Directing Groups
- —X
- —R
- —OR
- —OCOR
- —OH
- —NHCOR
- —NR2
- —NHR
- —NH2
Meta-Directing Groups
- —COOH
- —COOR
- —COR
- —CF3
- —CN
- —SO3+H
- —NO2
- —NR3+
Tri-Halogenation of EDG-Substituted Benzene
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.
Acid Catalyst for EDG–Benzene EAS Reactions
- 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.
Steric Effects w/ EDG-Substituted Benzenes
EAS
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.
Why is the resonance effect of halogens weaker than their inductive effect?
EAS
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.
Halogen Substituents in EAS Reactions
- 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.
Why are Nitrogen lone pair electrons more polarizable than Oxygen lone-pair electrons?
Nitrogen has a lower electronegativity than Oxygen, so its lone-pair electrons exhibit are better able to delocalize.
Which electron-donating groups exhibit a minimal steric effect?
EAS
- —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.
Reactivity of Disubstituted Benzenes
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.
Regioselectivity of Disubstituted Benzenes
EAS
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.
Amino Group to Benzene
—NH2
Reduction of Nitro Group
Nitro = —NO2
Primary Alkyl to Benzene
—R
Reduction of Acyl Group
Acyl = —COR
Alkoxy to Benzene
—OR
Williamson Ether Synthesis w/ Phenol
Amide to Benzene
—NHOR
Acetylation of Amino Group
Acetyl = CH3—CO—Cl
Synthesis of Benzylic Alcohol
- Grignard Reagent
- Organolithium Reagent
Monofunctionalization of Phenol
Alcohol-Substituted Benzene
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.
Monofunctionalization of Aniline
Amino-Substituted Benzene
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.
Functionalization of Benzenes w/ Strong EDG Substituents
EAS
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.
Unreactive Aryl Compounds in Friedel-Crafts Acylation
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.
Requirements of Nucleophilic Aromatic Substitution
NAS = Nucleophilic Aromatic Susbtitution
- Benzene compound must be highly electron-deficient (i.e. must be atleast two strong EDG substituents).
- The EDG substituents must be placed at the ortho–position and para–position.
- Nucleophilic substitution must occur at the carbon possessing a halide substituent.
- A strong nucleophilie is required for nucleophilic substitution to occur.
The placement of EDG substituents at the para-position and ortho-position enables delocalized stabilization of the negative charge. (The placement of EDG substituents at the meta-positions will not delocally stabilize the negative charge, so nucleophilic attack to meta-substituted Aryl compounds will not occur.)
RDS of NAS
RDS = Rate-Determining Step
NAS = Nucleophilic Aromatic Substitution
Nucleophilic Addition to the Aryl Compound
- The nucleophilic addition to the benzene ring is slow due to the resulting loss of aromaticity.
- The second step (i.e. elimination of the halide) is rapid due to the regeneration of aromaticity.
Nucleophiles w/ NAS Capability
- –OH (e.g. NaOH)
- –OR (e.g. NaOCH3)
- –NH2 (e.g. KNH2)
- NH3
- –CN (e.g. NaCN)
- –X (e.g. NaI)
Aryl Cation
A highly unstable substituted-benzene cation that is not stabilized by aromaticity or resonance.
The positive charge results from an empty sp2–hybridized carbon orbital, which is not in-plane with the arene ring (and thus cannot be stabilized by the arene π-orbital overlap).
Nitrile to Benzene
—C☰N
React Diazonium Group w/ Copper(I) Cyanide
—N☰N + CuCN → —C☰N
Functions of Reduction/Removal of Diazonium Group
- Convert C—NO2 to C—H
- Convert C—NH2 to C—H
- Convert C—N2 to C—H
Reduction can function to replace nitro groups, amino groups, and diazonium groups with hydrogen atoms.
EAS of Halogens into Aryl Compounds
Halogenation
- Bromination of Benzene w/ Acid Catalyst
- Bromination of Benzene w/ Copper(I) Ion
Jones Oxidation
Conversion of a Secondary Carbon to a Ketone
Two C—H bonds are replaced with two C—O bonds.
