12.15 Multiple Substituent Effects

1. 12.15Multiple Substituent Effects

2. O CH3 O O CH3COCCH3 CH3 The Simplest Case all possible EAS sites may be equivalent CH3 CCH3 AlCl3 + CH3 99%

3. CH3 Br2 Fe NO2 Another Straightforward Case CH3 Br directing effects of substituents reinforceeach other; substitution takes place orthoto the methyl group and meta to the nitro group NO2 86-90%

4. Generalization regioselectivity is controlled by themost activating substituent

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

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

7. 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%

8. 12.16Regioselective Synthesis of Disubstituted Aromatic Compounds

9. Factors to Consider order of introduction of substituents to ensure correct orientation

10. Br O CCH3 Synthesis of m-Bromoacetophenone Which substituent should be introduced first?

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

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

13. 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

14. NO2 O CCH3 Synthesis of m-Nitroacetophenone Which substituent should be introduced first?

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

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

17. 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

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

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

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