The Simplest Case

1. NHCH3 NHCH3 Br Cl Cl The Simplest Case all possible EAS sites may be equivalent strongly activating Br2 aceticacid 87%

2. CH3 HNO3 H2SO4 C(CH3)3 When activating effects are similar... CH3 substitution occurs ortho to the smaller group NO2 C(CH3)3 88%

3. CH3 CH3 HNO3 H2SO4 CH3 CH3 NO2 Steric effects control regioselectivity whenelectronic effects are similar position between two substituents is lastposition to be substituted 98%

4. Br O CCH3 Synthesis of m-Bromoacetophenone If bromine is introduced first, p-bromoacetophenone is major product. para meta

5. Br O CCH3 O O CH3COCCH3 O CCH3 Synthesis of m-Bromoacetophenone Br2 AlCl3 AlCl3

6. Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics

7. NO2 O CCH3 Synthesis of m-Nitroacetophenone If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.

8. O CCH3 O O CH3COCCH3 O CCH3 Synthesis of m-Nitroacetophenone O2N HNO3 H2SO4 AlCl3

9. Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Craftsreactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics sometimes electrophilic aromatic substitution must be combined with a functional group transformation

10. CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene Which first? (oxidation of methyl group or nitration of ring)

11. CO2H CH3 CH3 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene nitration givesm-nitrobenzoicacid oxidation givesp-nitrobenzoicacid

12. CO2H CH3 CH3 NO2 NO2 Synthesis of p-Nitrobenzoic Acid from Toluene HNO3 Na2Cr2O7, H2O H2SO4, heat H2SO4