Electrophilic Aromatic Substitution

1. Electrophilic Aromatic Substitution Part 2

2. Meta Directors A. Highly Electron Withdrawing Groups -CF3 B. Atom in a Multiple Bond to a More Electronegative Atom

3. CF3 CF3 + + H3C F3C C C H2SO4 NO2 + HNO3 META DIRECTORS NET RXN • A methyl group is electron-donating and stabilizes a carbocation. • Because F is so electronegative, a CF3 group destabilizes a carbocation.

4. CF3 CF3 CF3 NO2 H H H H H + H + + H H H H H H NO2 NO2 H H H gives ortho gives para gives meta less stable more stable Carbocation Stability Controls Regioselectivity

5. CF3 CF3 CF3 NO2 NO2 NO2 H H H + H H H + + H H H H H H H H H ortho Nitration of (Trifluoromethyl)benzene this resonance form is destabilized

6. CF3 CF3 CF3 H H H H H H + + + H H H H H H NO2 NO2 H H NO2 H para Nitration of (Trifluoromethyl)benzene this resonance form is destabilized

7. CF3 CF3 CF3 H H H H H H + + + H H H H H H NO2 NO2 NO2 H H H meta Nitration of (Trifluoromethyl)benzene none of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge on the carbon that bears the CF3 group

8. Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution EWG EWG X H H H + + H H H H H X H H —CF3 is a powerful EWG. It is strongly deactivating and meta directing

9. Meta Directors A. Highly Electron Withdrawing Groups -CF3 B. Atom in a Multiple Bond to a More Electronegative Atom

10. Groups With an Atom in a Multiple Bond to a More Electronegative Atom Have a Positive Formal Charge or d+ on Atom Directly Bonded to Ring • Resonance Effect • Inductive Effect

11. NET REACTION

12. Ortho/ Para Attack

13. Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution EWG EWG X H H H + + H H H H H X H H —CF3 is a powerful EWG. It is strongly deactivating and meta directing

14. Meta Attack

15. O2N Cl HO3S O O O O 2 SO3 Cl2 HNO3 CH CCl SO3H CCl CH H2SO4 FeCl3 H2SO4

16. Substituent Effects in Electrophilic Aromatic Substitution • Classification of Substituents in Electrophilic Aromatic Substitution Reactions Strongly activating Weakly Activating Standard of comparison is H Weakly Deactivating Strongly deactivating

17. Rate of Nitration Depends on What is Already on the Ring Ring Deactivators Ring Activators

18. Generalizations 1. All activating substituents are ortho-para directors. 2. Halogen substituents are slightly deactivating but ortho-para directing. 3. Strongly deactivating substituents are meta directors.

19. Rate EffectsAnything that makes the ring more nucleophilic increases reaction rate • Inductive Effects • Responsible for weakly activating/deactivating • Resonance Effects • Responsible for strongly activating/deactivating

20. Weakly Electron-Releasing Groups (ERGs)Inductive EffectWeak Activators are ortho-para directing and activating d+ d- ERG ERGs include —R, —Ar, and —C=C R groups are electron donating by dipole; Aromatic ring more nucleophilic and more susceptible to attack by electrophile

21. • ERG • Strongly Electron-Releasing Groups (ERGs)Resonance EffectStrong Activators are ortho-para directing and activating ERGs with a lone pair on the atom directlyattached to the ring are ortho-para directingand strongly activating

22. O •• •• •• • • • • ERG = • OH OR OCR • • • O • • • • NH2 NHR NR2 NHCR • • • • Groups that are electron releasing by resonance delocalize a negative formal charge through out the benzene ring All of these are ortho-para directingand strongly to very strongly activating

23. Strong Activators Delocalize a (-) Formal Charge About Ring to Make it More Nucleophilic* Resonance Effect

24. Weakly Electron-Withdrawing Groups (EWGs)Inductive Effect • Halogens are very electronegative and • withdraw electron density away from ring Benzene ring is becomes more positive and less susceptible to attack by positive nucleophile

25. For halogens; the inductive effect outweighs the resonance effect (even though halogens have lone pair on them) -F; most electronegative element -Cl, -Br, - I ; not as electronegative as F BUT larger than C so that resonance effect is not as important

26. CH3 Cl 42 42 0.029 0.029 2.5 2.5 0.009 0.009 58 0.137 Nitration of Toluene vs. Chlorobenzene -CH3 is an ortho, para director and ring activator -Cl is an ortho, para director but a ring deactivator -

27. Strongly Electron-Withdrawing Groups (EWGs)Resonance EffectStrong Deactivators are meta directing and deactivating EWG Groups that are electron withdrawing by resonance delocalize a positive formal charge through out the benzene ring

28. Strong Deactivators Delocalize a (+) Formal Charge About Ring to Make it Less Nucleophilic* Resonance Effect

29. Weak Deactivators Withdraw Electron Density From Ring to Make it Less Nucleophilic* Inductive Effect

30. CH3 CH3 Br Br2 FeBr3 NO2 NO2 86-90% Multiple Subsistent Effects • If both constituents direct to the same spot; then that location is major site of substitution.

31. O CH3 O CH3 Multiple Subsistent Effects CH3 CCH3 AlCl3 + CH3CCl CH3 99%

32. NHCH3 NHCH3 Br Br2 FeBr3 Cl Cl 87% 2. If the 2 groups direct to different positions; regioselectivity is controlled by themost activating substituent strongly activating

33. CH3 CH3 HNO3 NO2 H2SO4 C(CH3)3 C(CH3)3 88% If the 2 groups direct to different sites; and activating effects are similar... 3. Substitution occurs ortho to the smaller group

34. CH3 CH3 HNO3 H2SO4 CH3 CH3 NO2 98% Steric effects control regioselectivity whenelectronic effects are similar 4. Position between two substituents is lastposition to be substituted

35. 5. If 2 deactivating groups are on the benzene ring; substitution is rare

36. Factors to Consider in Compound Synthesis • Order of introduction of substituents to ensure correct orientation • Sometimes electrophilic aromatic substitution must be combined with a functional group transformation

37. H H SO2OH Br FeBr3 heat + + HOSO2OH Br2 + + H2O HBr Reaction Review A. Electrophilic Aromatic Substitution

38. O O H H H CCH2CH3 NO2 C(CH3)3 H2SO4 AlCl3 AlCl3 + + + (CH3)3CCl CH3CH2CCl HONO2 + + + HCl HCl H2O

39. Reaction ReviewB. Benzylic H is Reactive Site in R Groups

40. Br O CCH3 Synthesis of m-Bromoacetophenone Which substituent should be introduced first? If bromine is introduced first, p-bromoacetophenone is major product. para meta

41. Br O CCH3 O Br2 FeCl3 O CCH3 Synthesis of m-Bromoacetophenone CH3CCl AlCl3

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

43. H H O 1 H H CCH3 O 2 CH3CCl H H AlCl3 H H Substitution in Naphthalene Two possible sites for electrophilic aromatic substitution faster at C-1 than at C-2

44. Substitution Happens at the C-1 Position in Napthalene

45. E H + EAS in Naphthalene E H when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained + There are 4 Resonance Structure With the Benzene Ring Intact in C-1 Substitution

46. Electrophilic Aromatic Substituion Mechansim • Form Strong Electrophile • Electrophile adds to aromatic ring • See next slide. There are 4 resonance • Structures with one aromatic ring intact. • Restoration of aromaticity

47. For C-1 Substitution; 4 of the 7 Resonance Structures have a Benzene ring intact.

48. E E + H H + 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 • There are only 2 Resonance Structures with the • Benzene Ring Intact in C-2 Substitution

49. For C-2 Substitution; Only 2 of the 6 Resonance Structures have a Benzene ring intact.

50. 12.18Substitution inHeterocyclic Aromatic Compounds