Reactions of Benzene Reactions of Benzene 1

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

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

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

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

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

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

Y> 2018-05-08 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

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

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

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

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

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

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

Quiz 2 Quiz 3 diazonium salt 19

Sandmeyer Reaction 21

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 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

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

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