Electrophilic Aromatic Substitution

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

2. Products of Nitration 1 hr 48 hr 0.0003 hr

3. 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.

4. 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.

5. Classification of Substituents

6. Product Distribution in Nitration (Percent %) (Percent %) XorthometaparaXorthometapara (meta-directing Deactivators)(ortho- and para-directing Deactivators) -N(CH3)3 2 89 11 -F 13 1 86 -NO2 7 91 2 -Cl 35 1 64 -CO2H 22 77 2 -Br 43 1 56 -CN 17 81 2 -I 45 1 54 -CO2CH2CH3 28 72 2(ortho- and para-directing Activators) -COCH3 26 72 2 -CH3 63 3 34 -CHO 19 72 9 -OH 50 0 50 -NHCOCH3 19 2 79

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

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

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

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

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

12. 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)

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

14. Additivity of substituent effects… • Rule 4: With a bulky o,p- director and/or a bulky electrophile, para substitution predominates. (o,p; BULKY) (HSO3+ is a BULKY electrophile)

16. Mechanism

18. Halogenation of Benzene Requires a Lewis acid catalyst Reactivity: F2 >> Cl2 > Br2 >> I2

19. Catalyst

20. Mechanism(Cont’d)

21. Nitration of Benzene Electrophile = NO2⊕ (nitronium ion)

22. Mechanism

23. Sulfonation r.d.s repeat next slide

24. repeat

25. (heat) Sulfonation & Desulfonation-useful!

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

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

28. RX and Mechanism

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

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

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

32. Questions? Ch. 15 - 3

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

34. Basic amino groups (–NH2,–NHR, & –NR2) form strong electron withdrawing gps with acids Not Friedel-Crafts reactive

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

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

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

38. Reactivity towards electrophilic aromatic substitution

39. Rate-determining-step: aromatic ring -electrons attacking the E • Regiochemistry: directing effect • General aspects • Eithero-, p- directing orm-directing Ch. 15 - 57

40. Ch. 15 - 59