Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4 Ar-NO 2 + H 2 O 2.

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1 Electrophilic Aromatic Substitution (Aromatic compounds) Ar- = aromatic compound 1. Nitration Ar- + NO 3, 2 SO 4 Ar- + 2 O 2. Sulfonation Ar- + 2 SO 4, SO 3 Ar-SO O 3. alogenation Ar- + X 2, Fe Ar-X + X 4. Friedel-Crafts alkylation Ar- + R-X, AlCl 3 Ar-R + X

2 Friedel-Crafts alkylation (variations) a) Ar- + R-X, AlCl 3 Ar-R + X b) Ar- + R-O, + Ar-R + 2 O c) Ar- + Alkene, + Ar-R

3 NO 3 2 SO 4 SO 3 2 SO 4 SO 3 2, Fe C 3 C 2 - AlCl 3 C 2 C 3

4 toluene C 3 C 3 C 3 NO 3 2 SO 4 + C 3 SO 3 C 3 SO 3 C 3 faster than the same reactions with benzene 2 SO 4 + SO 3 C 3 C 3 2, Fe + C 3

5 nitrobenzene NO 3 2 SO 4 SO 3 2 SO 4 SO 3 slower than the same reactions with benzene Cl 2, Fe Cl

6 Substituent groups on a benzene ring affect electrophilic aromatic substitution reactions in two ways: 1) reactivity activate (faster than benzene) or deactivate (slower than benzene) 2) orientation ortho- + para- direction or meta- direction

7 -C 3 activates the benzene ring towards EAS directs substitution to the ortho- & para- positions - deactivates the benzene ring towards EAS directs substitution to the meta- position

8 increasing reactivity Common substituent groups and their effect on EAS: -N 2, -NR, -NR 2 -O -OR -NCOC 3 -C 6 5 -R - -X -CO, -COR -SO 3 -COO, -COOR -CN -NR ortho/para directors meta directors

9 OC 3 2, Fe OC 3 OC 3 + faster than benzene CO CO NO 3, 2 SO 4 slower than benzene 2 SO 4, SO 3 SO 3 + slower than benzene SO 3

10 If there is more than one group on the benzene ring: 1. The group that is more activating (higher on the list ) will direct the next substitution. 2. ou will get little or no substitution between groups that are meta- to each other.

11 C 3 2, Fe C 3 O O NCOC 3 NCOC 3 NO 3, 2 SO 4 C 3 C 3 CO Cl 2, Fe CO Cl + CO OC 3 Cl OC 3 OC 3

12 Orientation and synthesis. Order is important! synthesis of m-bromonitrobenzene from benzene: NO 3 2, Fe 2 SO 4 synthesis of p-bromonitrobenzene from benzene: 2, Fe NO 3 2 SO 4 + ou may assume that you can separate a pure paraisomer from an ortho-/para- mixture.

13 note: the assumption that you can separate a pure para isomer from an ortho/para mixture does not apply to any other mixtures. synthesis of 1,4-dibromo-2-nitrobenzene from benzene 2, Fe 2, Fe + NO 3 2 SO 4 separate pure para isomer from ortho/para mixture NO 3 2 SO 4 2, Fe 2, Fe + cannot assume that these can be separated!

14 synthesis of benzoic acids by oxidation of C 3 C 3 C 3 KMnO 4 COO AlCl 3 heat C 3 C 3 KMnO 4 COO NO 3 COO AlCl 3 heat 2 SO 4 C 3 C 3 NO 3 C 3 KMnO 4 COO AlCl 3 2 SO 4 + ortho- heat

15 Links to problem sets on the web involving EAS: Reactivity and sites on monosubstituted benzene Reaction Sties on disubstituted benzenes Synthesis of disubstituted benzenes Synthesis of trisubstituited benzenes

16 nitration + O- + 2 SO 4 2 O- + SO O- 2 O + 2 SO O SO O + NO SO 4 3 O SO

17 nitration: 1) O SO 4 3 O SO ) + + RDS electrophile

18 resonance

19 Mechanism for nitration: 1) O SO 4 3 O SO ) + + RDS 3) + +

20 Mechanism for sulfonation: 1) 2 2 SO 4 3 O + + SO SO 3 2) + SO 3 RDS SO 3-3) SO 3 - SO ) SO O + SO O

21 Mechanism for halogenation: 1) Cl 2 + AlCl 3 Cl-Cl-AlCl 3 2) + Cl-Cl-AlCl 3 RDS Cl + AlCl 4-3) Cl + AlCl 4 - Cl + Cl + AlCl 3

22 Mechanism for Friedel-Crafts alkylation: 1) R-X + FeX 3 R + FeX 4-2) + R RDS R 3) R + FeX4 - R + X + FeX 3

23 Mechanism for Friedel-Crafts with an alcohol & acid 1) R-O + + RO 2 + 2) RO 2 + R + 2 O 3) + R RDS R 4) R R + +

24 Mechanism for Friedel-Crafts with alkene & acid: 1) C C + + R 2) + R RDS R 3) R R + + electrophile in Friedel-Crafts alkylation = carbocation

25 Generic Electrophilic Aromatic Substitution mechanism: 1) + + Z - RDS + Z - 2) + Z - + Z

26 Why do substituent groups on a benzene ring affect the reactivity and orientation in the way they do? electronic effects, pushing or pulling electrons by the substituent. Electrons can be donated ( pushed ) or withdrawn ( pulled ) by atoms or groups of atoms via: Induction due to differences in electronegativities Resonance delocalization via resonance

27 N R N unshared pair of electrons on the nitrogen resonance donating groups (weaker inductive withdrawal) R N R R R N R strong inductive withdrawal (no unshared pair of electrons on the nitrogen & no resonance possible

28 O resonance donation (weaker inductive withdrawal) O R resonance donation (weaker inductive withdrawal) O 3 C C N resonance donation (weaker inductive withdrawal)

29 resonance donation 3 C inductive donation sp3 sp2 ring carbon X inductive withdrawal

30 O C O C R O C O resoance withdrawal and inductive withdrawal O C RO

31 N C resonance and inductive withdrawal O N O resonance and inductive withdrawal

32 increasing reactivity Common substituent groups and their effect on reactivity in EAS: -N 2, -NR, -NR 2 -O -OR -NCOC 3 -C 6 5 -R - -X -CO, -COR -SO 3 -COO, -COOR -CN -NR electron donating electron withdrawing

33 Electron donating groups activate the benzene ring to electrophilic aromatic substitution. 1. electron donating groups increase the electron density in the ring and make it more reactive with electrophiles. 2. electron donation stabilizes the intermediate carbocation, lowers the Eact and increases the rate. C 3

34 Electron withdrawing groups deactivate the benzene ring to electrophilic aromatic substitution. 1. electron withdrawing groups decrease the electron density in the ring and make it less reactive with electrophiles. 2. electron withdrawal destabilizes the intermediate carbocation, raising the Eact and slowing the rate.

35 CF 3 electron withdrawing = deactivating & meta-director PO 3 electron withdrawing = deactivating & meta-director P 2 electron donating = activating & ortho-/para-director

36 2, Fe + ortho- 2, Fe + ortho- O O 2, Fe O O + ortho-

37 ow to draw resonance structures for EAS

38 G G G ortho-attack G G G meta-attack G G G para-attack

39 G G If G is an electron donating group, these structures are especially stable.

40 G G G ortho-attack G G G meta-attack G G G para-attack

41 Electron donating groups stabilize the intermediate carbocations for ortho- and para- in EAS more than for meta-. The Eact s for ortho-/para- are lower and the rates are faster. Electron donating groups direct ortho-/para- in EAS

42 G G If G is an electron withdrawing group, these structures are especially unstable.

43 G G G ortho-attack G G G meta-attack G G G para-attack

44 Electron withdrawing groups destabilize the intermediate carbocations for ortho- and para- in EAS more than for meta-. The Eact s for ortho-/para- are higher and the rates are slower. Electron withdrawing groups direct meta- in EAS

45 alogens are electron withdrawing but are ortho/para directing in EAS. The halogen atom is unusual in that it is highly electronegative but also has unshared pairs of electrons that can be resonance donated to the carbocation.

46 X X X X ortho- X X X meta- X X X X para- halogens are deactivating in EAS but direct ortho and para

47 increasing reactivity Common substituent groups and their effect on EAS: -N 2, -NR, -NR 2 -O -OR -NCOC 3 -C 6 5 -R - -X -CO, -COR -SO 3 -COO, -COOR -CN -NR ortho/para directors meta directors