2. Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

3. Products of Nitration 1 hr 48 hr 0.0003 hr

4. Mechanism of Electrophilic Aromatic Substitution With a substituent group G Depending on the nature of the substituent, the substituent G may stabilize the carbocation intermediate and therefore speed the reaction, or it may raise the energy of the carbocation and slow the reaction. Substituents that make the ring react faster (than benzene) with electrophiles are called activators; those that make the ring react slower (than benzene) are called deactivators.

5. Substituent effects All activators also direct incoming electrophiles to the ortho- and the para-positions. Most deactivators direct incoming electrophiles to the meta position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing.

6. Classification of Substituents

7. Product Distribution in Nitration (Percent %) (Percent %) X ortho meta paraX ortho meta para (meta-directing Deactivators) (ortho- and para-directing Deactivators) -N(CH 3 ) 3 289 11-F 13 1 86 -NO 2 7912-Cl 35 1 64 -CO 2 H22772-Br 43 1 56 -CN17812-I 45 1 54 -CO 2 CH 2 CH 3 28722 (ortho- and para-directing Activators) -COCH 3 26722-CH 3 63 3 34 -CHO19729-OH 50 0 50 -NHCOCH 3 19 2 79

8. o,p-Activators (alkyl & aryl groups) 3º, especially stable

9. o,p-Activators with a lp of electrons 4 resonance forms o- m- p-

10. o,p-Deactivators (Halogens) 4 resonance forms o- m- p-

11. meta-directing Deactivators Especially UNSTABLE** o- m- p-

12. Additivity of substituent effects in disubstituted aromatic rings Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates. (o,p) (m)

13. Additivity of substituent effects… Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates, but mixtures often result. (o,p; STRONG activator) (o,p; weak activator)

14. Additivity of substituent effects… Rule 3: Substitution almost never occurs between two substituents meta to each other. (o,p) X (too crowded)

15. Additivity of substituent effects… Rule 4: With a bulky o,p- director and/or a bulky electrophile, para substitution predominates. (o,p; BULKY) (HSO 3 + is a BULKY electrophile)

17. Mechanism

19. Halogenation of Benzene Requires a Lewis acid catalyst Reactivity:F 2 >> Cl 2 > Br 2 >> I 2

20. Catalyst

21. Mechanism (Cont’d)

22. Nitration of Benzene Electrophile = NO 2 ⊕ (nitronium ion)

23. Mechanism

24. Sulfonation r.d.s repeat next slide

25. repeat

26. Sulfonation & Desulfonation-useful! (heat)

27. Friedel–Crafts Alkylation Electrophile = R ⊕ (not vinyl or aryl) R = 2 o or 3 o

28. Friedel–Crafts Acylation Acyl group: Electrophile is R–C≡O ⊕ (acylium ion)

29. RX and Mechanism

30. Ch. 15 - 33 Acid chlorides (or acyl chlorides) Prep

31. Ch. 15 - 35 (not formed) Limitations of Friedel–Crafts Reactions carbocations rearrangement

32. Ch. 15 - 36 1 o cation (not stable) Reason 3 o cation

33. Ch. 15 - 3 Questions?

34. Problems: Friedel–Crafts alkylations, acylations, etc. with withdrawing groups & amines (basic) generally give poor yields deactivating gps

35. Basic amino groups (–NH 2,–NHR, & –NR 2 ) form strong electron withdrawing gps with acids Not Friedel-Crafts reactive

36. Another problem: polyalkylations can occur More common with activated aromatic rings

37. Substituents effect reactivity & regiochemistry of substitution Y = EDG (electron-donating group) or EWG (electron-withdrawing group) possibilities meta m para p

38. Ch. 15 - 50 Ring is electron poor; Ring reacts slower than benzene with E + Ring is electron rich; Ring reacts faster than benzene with E + relative to benzene

39. Reactivity towards electrophilic aromatic substitution

40. Ch. 15 - 57 Regiochemistry: directing effect General aspects Either o-, p- directing or m-directing Rate-determining-step: aromatic ring  -electrons attacking the E

41. Ch. 15 - 59