CHEM 212 Synthetic Toolbox (Aromatic Substitution Reaction)

Bromination EAS

Br₂, FeBr₃ > Br substituent

Chlorination EAS

Cl₂, AlCl₃ > Cl substituent

Halogenation EAS

Brominatino or Chlorination, does not work well with Iodine or Fluorine

EAS

Electrophilic Aromatic Substitution, pi bond nucleophile attacks reactive electrophile, Electrophile and H on one C & C+, deprotonation regenerates aromaticity —> substitution of benzene ring by electrophile

Nitration EAS

HNO₃, H₂SO₄ > NO₂ substituent

Sulfonation EAS

H₂SO₄, Heat > SO₃H

Friedel Crafts Acylation EAS

R—C(=O)—Cl, AlCl₃ —> C(=O)—R substituent
Avoid NO₂, SO₃H groups on starting benzene

Friedel Crafts Alkylation EAS

R—C—Cl, AlCl₃ —> C—R substituent
Avoid NO₂, SO₃H groups on starting benzene
Carbocation rearrangements will occur with linear chains with 2+ carbons

Wolff Kischner Transformation

NH₂NH₂, —OH, Heat
Ketone carbon > CH₂ group

C(=O)—CH₃ —> CH_2^—CH₃

Clemmensen Reduction

Zn(Hg), HCl
Ketone carbon > CH₂ group
C(=O)—CH₃ > CH₂—CH₃

Removal of SO₃H group

H₃O⁺, H₂O
SO₃H —> z

Conversion of Nitrobenzene to Aniline

H₂, Pd/C OR SnCl₂, HCl
NO₂ —> NH₂

S_NAr

Nucleophilic Aromatic Substitution, nucleophile attacks Halobenzene carbon, Nucleophile and Halogen on one C & C:-, negative charge regenerates aromaticity and Halogen leaving group departs —> substitution of benzene ring by nucleophile

S_NAr addition of Alkoxy group

O^-R, Heat

Cl —> OR

Works best if ring contains EWG (e.g. NO₂, SO₃H)

Addition, Elimination mechanism

Formation of Diazonium Ion

1. H₂, Pd/C OR SnCl₂, HCl
   NO₂ > NH₂

2. NaNO₂, HCl
   NH₂ > N⁺≡N

Strongly activating, o/p

N with lone pair: —NH₂, —NHR, —NR₂

O with lone pair: —OH, —OR

Moderately activating, o/p

Amide, attached to benzene via N: —NHC(=O)R

Ester, attached to benzene via O: —OC(=O)R

Weakly activating, o/p

Alkyl/Aryl/Vinyl: —R, —Ar, —CH=CHR

Weakly deactivating, o/p

Halogens: —F, Cl, Br, I

Moderately deactivating, meta

Carbonyls, attached to benzene via C:

—C(=O)H

—C(=O)R

—C(=O)OR

—C(=O)OH

—C(=O)Cl

Strongly deactivating, meta

—C≡N

—SO₃H

—N⁺H₃, —N⁺H₂R, —N⁺HR₂, —N⁺R₃

—NO₂