Reactions of Benzene Reactions of Benzene 1

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Hilary Garrison
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1 Reactions of Benzene Reactions of Benzene 1

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3 Halogenation of Benzene v Benzene does not react with Br 2 or Cl 2 unless a Lewis acid is present (a catalytic amount is usually enough) 3

4 v Mechanism v Mechanism (Cont 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 (Cont d) v F 2 : too reactive, gives a mixture of mono-, di- and polysubstituted products Br H 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. HNO 3, Cu 2+, H 2 O 2 ) Friedel Crafts Alkylation v Mechanism Cl AlCl 3 Cl AlCl 3 v Electrophile in this case is R Å R = 2 o or 3 o d + d - or R ClAlCl (R = 1 o 3 ) + AlCl 4 5

6 v Mechanism (Cont d) v Mechanism (Cont d) H Cl AlCl 3 v Note: Not necessary to start with alkyl halide, other possible functional groups can be used to generate a reactive carbocation e.g. + H + + OH BF 3 60 o C via H O BF 3 6

7 Friedel Crafts Acylation v Acyl group: v Electrophile in this case is R C O Å (acylium ion) v Mechanism v Mechanism (Cont d) R O Cl + AlCl 3 O R C Cl AlCl 3 R C O AlCl 4 + R C O R C O O R O R O R 7

8 v Mechanism (Cont d) v Acid chlorides (or acyl chlorides) O O R R C Cl H Cl AlCl 3 Can be prepared by SOCl 2 O O R C or OH R C Cl PCl 5 Gatterman-Koch Formylation 8

9 Y> Vilsmeier Haack reaction Second Substitution phosphorus oxychloride Z donates electrons Z > Y withdraws electrons The ring is more electron rich and reacts faster with an electrophile The ring is electron poor and reacts more slowly with an electrophile 9

10 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 10

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Inductive & Resonance Effects: Theory of Orientation v Two types of EDG (i) OR NR 2 or by resonance effect (donates electron towards the benzene ring through resonance) (ii) CH 3 > by positive

12 Inductive & Resonance Effects: Theory of Orientation v Two types of EDG (i) OR NR 2 or by resonance effect (donates electron towards the benzene ring through resonance) (ii) CH 3 > by positive inductive effect (donates electron towards the benzene ring through the s bond) 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. O C CH 3 Deactivate the ring by the resonance effect F > C F F > > Deactivate the ring by the negative inductive effect 12

13 v For halogens, two opposing effects Cl > Cl Negative inductive effect: withdraws electron density from the benzene ring Resonance effect: donates electron density to the benzene ring Halogens are weak deactivating groups Negative inductive effect > resonance effect in this case 13

14 Energy Diagram 53 Summary Energy -NO 2 or -CO 2 H, ortho- and para- -NO 2 or -CO 2 H, meta- -Cl or -Br, meta- -Cl or -Br, ortho- and para- -H (unsubstituted) -R or -Ar, meta- -R or -Ar, ortho- and para- -NH 2 or -OH, meta- -NH 2 or -OH, ortho- and para- Deactivators Activators [Carbocation Intermediate] Reactants Reaction Progress 14

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16 v Sulfonation & Desulfonation SO 3, conc. H 2 SO 4 25 o C - 80 o C SO 3 H dil. H 2 SO 4 H 2 O, 100 o C 16

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18 Lysergic acid diethylamide (LSD) is a psychedelic drug effective at reducing alcohol consumption in alcoholism. Quiz 1 antidepressant 18

19 Quiz 2 Quiz 3 diazonium salt 19

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21 Sandmeyer Reaction 21

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23 S N 1 and S N 2 reactions did not occur at sp 2 centres. S N 2 Nucleophilc substitution reactions - do not occur with aryl compounds because the p electron cloud repels the back-side approach of a nucleophile S N 1 not reasonable because: 1) C Cl bond is strong; therefore, ionization to a carbocation is a highenergy process 2) aryl cations are less stable than alkyl cations Nucleophilic aromatic substitution reactions, S N Ar - general mechanism 23

Leaving Group Effects F > Cl > Br > I is unusual, but consistent with mechanism carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F

24 Leaving Group Effects F > Cl > Br > I is unusual, but consistent with mechanism carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F stabilizes negatively charged intermediate Nucleophilc aromatic substitution reactions - do occur with aryl halides containing electron-withdrawing groups position ortho or para to the halogen 24

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26 Synthesis of Quetiapine Amine groups are useful for directing, and after conversion to an arenediazonium salt, hypophosphorus acid can eliminate the group altogether: Powerful reducing agent for the treatment of schizophrenia, bipolar disorder 26

27 Vilsmeier Haack reaction synthesis of (S)-fluoxetine S-fluoxetine is slightly more potent in the inhibition of serotonin reuptake than R-fluoxetine antidepressant Prozac Asymmetric Hydroboration 27

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There are two main electronic effects that substituents can exert:

Substituent Effects There are two main electronic effects that substituents can exert: RESONANCE effects are those that occur through the π system and can be represented by resonance structures. These