Chapter 15. Reactions of Aromatic Compounds. 1. Electrophilic Aromatic Substitution Reactions

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1 hapter 15 eactions of Aromatic ompounds 1. Electrophilic Aromatic Substitution eactions v verall reaction reated by Professor William Tam & Dr. Phillis hang opyright S 3 2 S 4 S 3 2. A General Mechanism for Electrophilic Aromatic Substitutions v Different chemistry with alkene l All 3 l All 3 + Br 2 Br Br + Br 2 No eaction 1

2 v Benzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic substitution v Mechanism Step 1 E + E E E A E + A slow r.d.s. ( substituted by E) E v Mechanism Step 2 E B 2

3 eactions of Benzene eactions of Benzene 3. alogenation of Benzene v Examples v Benzene does not react with Br 2 or l 2 unless a Lewis acid is present (a catalytic amount is usually enough) eactivity: F 2 > l 2 > Br 2 > I 2 3

4 v Mechanism v Mechanism (ont d) Br Br FeBr 3 d + d - Br Br FeBr 3 (weak electrophile) Br slow r.d.s. Br + FeBr 4 Br Br Br (very reactive electrophile) v Mechanism (ont d) v F 2 : too reactive, gives a mixture of mono-, di- and polysubstituted products Br Br FeBr 3 4

5 v I 2 : very unreactive even in the presence of Lewis acids; usually need to add an oxidizing agent (e.g. N 3, u 2+, 2 2 ) 4. Nitration of Benzene v Electrophile in this case is N 2 Å (nitronium ion) 5

6 v Mechanism v Mechanism (ont d) S + N N 2 slow r.d.s. S N N + 2 N 2 N 2 N 2 (N 2 ) v Mechanism (ont d) N 2 2 N Sulfonation of Benzene v Mechanism Step 1 S 3 is protonated to form S 3 + 6

7 Step 2 Step 3 S 3 + reacts as an electrophile with the benzene ring to form an arenium ion Loss of a proton from the arenium ion restores aromaticity to the ring and regenerates the acid catalyst v Sulfonation & Desulfonation S 3, conc. 2 S 4 25 o - 80 o S 3 dil. 2 S 4 2, 100 o 7

8 6. Friedel rafts Alkylation v Mechanism l All 3 l All 3 v Electrophile in this case is Å = 2 o or 3 o d + d - or lall ( = 1 o 3 ) + All 4 v Mechanism (ont d) v Mechanism (ont d) l All 3 8

9 v Note: Not necessary to start with alkyl halide, other possible functional groups can be used to generate a reactive carbocation e.g BF 3 60 o via BF 3 7. Friedel rafts Acylation v Acyl group: v Electrophile in this case is Å (acylium ion) 9

10 v Mechanism v Mechanism (ont d) l + All 3 l All 3 All 4 + v Mechanism (ont d) v Acid chlorides (or acyl chlorides) l l All 3 an be prepared by Sl 2 or l Pl 5 10

11 8. Limitations of Friedel rafts eactions v For example (not formed) v When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations. All 3 (ow is this formed?) v eason 1 o cation (not stable) l + All 3 + 1,2-hydride shift All 4 v Friedel rafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an N 2, N, or N 2 group. This applies to both alkylations and acylations. N 2 N( 3 ) 3 F 3 S 3 N 2 3 o cation (more stable) These usually give poor yields in Friedel-rafts reactions 11

12 v The amino groups, N 2, N, and N 2, are changed into powerful electronwithdrawing groups by the Lewis acids used to catalyze Friedel-rafts reactions N + All 3 N All 3 > v Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily sp 2 l, All 3 sp 2 No Friedel-rafts reaction Does not undergo a Friedel-rafts reaction l, All 3 No Friedel-rafts reaction v Polyalkylations often occur BF o (24%) (14%) 9. Synthetic Applications of Friedel-rafts Acylations: The lemmensen eduction & Wolff Kishner eductions v earrangements of the carbon chain do not occur in Friedel rafts acylations v The acylium ion, because it is stabilized by resonance, is more stable than most other carbocations. Thus, there is no driving force for a rearrangement. 12

13 v The carbonyl group of an aryl ketone can be reduced to a 2 group 9A. The lemmensen eduction [] Zn/g l reflux v lemmensen reduction of ketones A very useful reaction for making alkyl benzenes that cannot be made via Friedel-rafts alkylations e.g.? 13

14 v lemmensen reduction of ketones annot use Friedel-rafts alkylation v earrangements of carbon chains do not occur in Friedel-rafts acylations (no rearrangement of the group) 9B. The Wolff Kishner eduction Zn/g conc. l reflux 14

15 Quiz 1 Quiz 2 Quiz 3 15

16 10. Substituents an Affect Both the eactivity of the ing and the rientation of the Incoming Group v Two questions have to be addressed: eactivity egiochemistry eactivity faster or slower than Y = EDG (electron-donating group) or EWG (electron-withdrawing group) egiochemistry G + d + d - E A G E other resonance structure Statistical mixture of o-, m-, p- products, or any preference? A substituted benzene Electrophilic reagent Arenium ion 16

17 Y> Z donates electrons The ring is more electron rich and reacts faster with an electrophile Z > Y withdraws electrons The ring is electron poor and reacts more slowly with an electrophile eactivity Increasing activity Substituent EDG EWG eactivity towards electrophilic aromatic substitution 17

18 The energy diagrams below illustrate the effect of electronwithdrawing and electron-donating groups on the transition state energy of the rate-determining step. Figure 18.6 Energy diagrams comparing the rate of electrophilic substitution of substituted benzenes v egiochemistry: directing effect General aspects t Either o-, p- directing or m- directing t ate-determining step is p- electrons on the benzene ring attacking an electrophile (E Å ) Y Y E E attack attack Y Y Y Y Y Y E E E -I -II -III E E E -I -II -III 18

19 Y E v lassification of different substituents Y Y (EDG) v lassification of different substituents Y Y (EWG) N 2, N 2, - N (alkyl) Ph Strongly activating Moderately activating Weakly activating NA NA o-, p- directing o-, p- directing o-, p- directing alide (F, l, Br, I),,,, S 3, N F 3, l 3, N 2, N 3 Weakly deactivating Moderately deactivating Strongly deactivating o-, p- directing m- directing m- directing 19

20 11. ow Substituents Affect Electrophilic Aromatic Substitution: A loser Look 11B.Inductive & esonance Effects: Theory of rientation v Two types of EDG (i) (ii) N 2 3 > or by resonance effect (donates electron towards the benzene ring through resonance) by positive inductive effect (donates electron towards the benzene ring through the s bond) v Two types of EDG The resonance effect is usually stronger than the positive inductive effect if the atoms directly attached to the benzene ring are in the same row as carbon in the periodic table 20

21 v Similar to an EDG, an EWG can withdraw electrons from the benzene ring by the resonance effect or by the negative inductive effect e.g. 3 Deactivate the ring by the resonance effect 11. Meta-Directing Groups (EWG halogen) F > F F > > Deactivate the ring by the negative inductive effect v EWG =,,, F 3, N 2, etc. v For example (highly unstable due to negative inductive effect of F 3 ) (highly unstable due to the negative inductive effect of F 3 ) 21

22 (positive charge never attaches to the carbon directly attached to the EWG: F 3 ) Þ relatively more favorable 11D. rtho/para-directing Groups v EDG = N 2,,, etc. 22

23 v For example (para) N N 2 N 2 N (extra resonance structure due to positive mesomeric effect of 3 ) N 2 (extra resonance structure due to resonance effect of 3 ) N 2 (para) (favorable) (3 resonance structures only, no extra stabilization by resonance effect of 3 ) Þ less favorable 23

24 v For halogens, two opposing effects l > Negative inductive effect: withdraws electron density from the benzene ring l esonance effect: donates electron density to the benzene ring v verall alogens are weak deactivating groups t Negative inductive effect > resonance effect in this case v egiochemistry With the exception of fluorine, halogens must use 3p, 4p, and 5p orbitals to overlap with the 2p orbital of carbon - this overlap becomes progressively weaker as the size of the halogen increases. (extra resonance structure due to resonance effect of l) 24

25 (3 resonance structures only, no extra stabilization by the resonance effect of l) Þ less favorable (extra resonance structure due to resonance effect of l) rtho/para-directing Deactivators: alogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect. Energy Diagram 99 25

26 11E. rtho/para Direction and eactivity of Alkylbenzenes v rtho attack 3 E elatively stable contributor E E > E v Meta attack v Para attack 3 E elatively stable contributor > E E E 26

27 Energy Summary [arbocation Intermediate] -N 2 or - 2, ortho- and para- -N 2 or - 2, meta- -l or -Br, meta- -l or -Br, ortho- and para- - (unsubstituted) - or -Ar, meta- - or -Ar, ortho- and para- -N 2 or -, meta- -N 2 or -, ortho- and para- Deactivators Activators 11F. Summary of Substituent Effects on rientation and eactivity Y Y (EDG) N 2, N 2, - N (alkyl) Ph Strongly activating Moderately activating Weakly activating o-, p- directing o-, p- directing o-, p- directing eactants NA NA eaction Progress Y Y (EWG) alide (F, l, Br, I),,,, S 3, N F 3, l 3, N 2, N 3 Weakly deactivating Moderately deactivating Strongly deactivating o-, p- directing m- directing m- directing 27

28 12. eactions of the Side hain of Alkylbenzenes 12A. Benzylic adicals and ations Methylbenzene (toluene) The benzyl radical Methylbenzene (toluene) Ethylbenzene Isopropylbenzene (cumene) Phenylethene (styrene or vinylbenzene) Benzylic radicals are stabilized by resonance 28

29 12B.Benzylic alogenation of the Side hain Benzylic cations are stabilized by resonance v Mechanism hain initiation X X peroxides heat or light 2 X hain propagation X X 6 5 X + X hain propagation hain termination X X X 6 5 X 29

30 v e.g. 13. Alkenylbenzenes 13A. Stability of onjugated Alkenylbenzenes v Example + heat v Alkenylbenzenes that have their side-chain double bond conjugated with the benzene ring are more stable than those that do not (not observed) conjugated system is more stable than non-conjugated system a b - a - b 30

31 13B. Additions to the Double Bond of Alkenylbenzenes v Mechanism (top reaction) 2 Br heat Br + Br Br + Br Br Br + Br Br (more stable benzylic radical) (less stable) (no peroxides) Br + Br Br v Mechanism (bottom reaction) 13. xidation of the Side hain d + d - Br (more stable benzylic cation) (less stable) Br Br 31

32 v Using hot alkaline KMn 4, alkyl, alkenyl, alkynyl and acyl groups all oxidized to group v For alkyl benzene, 3 o alkyl groups resist oxidation Need benzylic hydrogen for alkyl group oxidation 14. Synthetic Applications v 3 group: ortho-, para-directing v N 2 group: meta-directing ow? 3 3 l 3 All 3 conc. N 3 conc. 2 S 4 heat 3 N 2 N N2 32

33 v If the order is reversed Þ the wrong regioisomer is produced conc. N 3 3 l 3 conc. 2 S 4 heat N 2 All 3 NT N 2 3 N 2 v We do not know how to substitute a hydrogen on a benzene ring with a group. owever, side chain oxidation of alkylbenzene could provide the group N 2 v Both the group and the N 2 group are meta-directing v oute 1 v oute l All 3 1. KMn 4, -, D conc. N 3 N 2 conc. 2 S 4 heat 33

34 v Which synthetic route is better? ecall Limitations of Friedel-rafts eactions, Section 15.8 t Friedel rafts reactions usually give poor yields when powerful electronwithdrawing groups are present on the aromatic ring or when the ring bears an N 2, N, or N 2 group. This applies to both alkylations and acylations t oute 2 is a better route v Both Br and Et groups are ortho-, paradirecting v ow to make them meta to each other? v ecall: an acyl group is meta-directing and can be reduced to an alkyl group by lemmensen reduction Br l All 3 Br 2 FeBr 3 14A. Use of Protecting and Blocking Groups v Protected amino groups Example Br Br Zn/g l, heat 34

35 Problem v Not a selective synthesis, o- and p- products + dibrominated and tribrominated products will form v The amino groups, N 2, N, and N 2, are changed into powerful electronwithdrawing groups by the Lewis acids used to catalyze Friedel-rafts reactions N N All 3 > + All 3 Does not undergo a Friedel-rafts reaction Solution v Introduce a deactivating group on N 2 v The amide group is less activating than N 2 group No problem for over bromination v The steric bulkiness of this group also decreases the formation of the o- brominated product 35

36 Problem v Difficult to get o-product without getting p-product v ver nitration Solution v Use of a S 3 blocking group at the p-position which can be removed later 14B. rientation in Disubstituted Benzenes v Directing effect of EDG usually outweighs that of EWG v With two EDGs, the directing effect is usually controlled by the stronger EDG 36

37 Examples [only major product(s) shown] 37

38 38

39 15. Allylic and Benzylic alides in Nucleophilic Substitution eactions Ar 2 X 1 o Allylic 2 o Allylic 3 o Allylic X Ar ' 1 o Benzylic 2 o Benzylic 3 o Benzylic X X Ar ' X X v A Summary of Alkyl, Allylic, & Benzylic alides in S N eactions These halides give mainly S N 2 reactions: 3 X 2 X X These halides may give either S N 1 or S N 2 reactions: Ar 2 X Ar X 2 ' X X v A Summary of Alkyl, Allylic, & Benzylic alides in S N eactions These halides afford mainly S N 1 reactions: ' " X Ar ' X ' X 16. eduction of Aromatic ompounds 2 /Ni slow + 2 /Ni fast benzene cyclohexadienes cyclohexene 2 /Ni fast cyclohexane 39

40 16A. The Birch eduction v Mechanism The solvated electrons add to the aromatic ring to give a radical anion. benzene Na N 3, Et electride salt [Na(N 3 ) x ] + e 1,4-cyclohexadiene benzene Na Na - - benzene radical anion Et etc. etc. - cyclohexadienyl radical Et etc. - cyclohexadienyl anion 1,4-cyclohexadiene kinetic product is produced because the largest orbital coefficient of the M of the conjugated pentadienyl anion intermediate is on the central carbon atom. 40

41 v Synthesis of 2-cyclohexenones 3 Li liq. N 3 Et 3 (84%) cyclohexenone 41

42 Quiz 1 Quiz 2 Quiz 3 42