1. 12.15 Multiple Substituent Effects

2. all possible EAS sites may be equivalent The Simplest Case AlCl 3 O CH 3 COCCH 3 O+ CH 3 CCH 3 O99%

3. directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group Another Straightforward Case CH 3 NO 2 CH 3 NO 2 Br 86-90% Br 2 Fe

4. Generalization regioselectivity is controlled by the most activating substituent

5. all possible EAS sites may be equivalent The Simplest Case Br 2 NHCH 3 Cl 87% acetic acid NHCH 3 Cl Br strongly activating

6. substitution occurs ortho to the smaller group When activating effects are similar... CH 3 C(CH 3 ) 3 CH 3 C(CH 3 ) 3 NO 2 HNO 3 H 2 SO 4 88%

7. position between two substituents is last position to be substituted Steric effects control regioselectivity when electronic effects are similar HNO 3 H 2 SO 4 98% CH 3 NO 2 CH 3

8. 12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds

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

10. Synthesis of m-Bromoacetophenone Br CCH 3 O Which substituent should be introduced first?

11. Synthesis of m-Bromoacetophenone Br CCH 3 Opara meta If bromine is introduced first, p-bromoacetophenone is major product.

12. Synthesis of m-Bromoacetophenone CCH 3 O O CH 3 COCCH 3 O AlCl 3 Br 2 AlCl 3 CCH 3 OBr

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. Synthesis of m-Nitroacetophenone NO 2 CCH 3 O Which substituent should be introduced first?

15. Synthesis of m-Nitroacetophenone NO 2 CCH 3 O If NO 2 is introduced first, the next step (Friedel-Crafts acylation) fails.

16. Synthesis of m-Nitroacetophenone CCH 3 O O CH 3 COCCH 3 O AlCl 3 HNO 3 H 2 SO 4 CCH 3 O O2NO2NO2NO2N

17. 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 sometimes electrophilic aromatic substitution must be combined with a functional group transformation

18. Synthesis of p-Nitrobenzoic Acid from Toluene Which first? (oxidation of methyl group or nitration of ring) CH 3 CO 2 H NO 2 CH 3

19. Synthesis of p-Nitrobenzoic Acid from Toluene CH 3 CO 2 H NO 2 CH 3 nitration gives m-nitrobenzoic acid oxidation gives p-nitrobenzoic acid

20. Synthesis of p-Nitrobenzoic Acid from Toluene CH 3 NO 2 CH 3 HNO 3 H 2 SO 4 NO 2 CO 2 H Na 2 Cr 2 O 7, H 2 O H 2 SO 4, heat

21. 12.17 Substitution in Naphthalene

22. two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2 Naphthalene 1 2 HH HH HH HH

23. EAS in Naphthalene AlCl 3 O CH 3 CCl 90% CCH 3 O is faster at C-1 than at C-2

24. EAS in Naphthalene when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained E H E H + +

25. EAS in Naphthalene when attack is at C-2 in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed E H +EH +

26. 12.18 Substitution in Heterocyclic Aromatic Compounds

27. There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive.. Generalization

28. Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes  electrons to be held more strongly than in benzene. Pyridine N

29. Pyridine can be sulfonated at high temperature. EAS takes place at C-3. Pyridine N SO 3, H 2 SO 4 HgSO 4, 230°C SO 3 H N 71%

30. Pyrrole, Furan, and Thiophene O S N H Have 1 less ring atom than benzene or pyridine to hold same number of  electrons (6).  electrons are held less strongly. These compounds are relatively reactive toward EAS..

31. undergoes EAS readily C-2 is most reactive position Example: Furan BF 3 O CH 3 COCCH 3 O+ CCH 3 O75-92% O O