1. 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department of Chemistry University of Toronto

2. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 2 Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6  electrons Reactions of benzene lead to the retention of the aromatic core Electrophilic aromatic substitution replaces a proton on benzene with another electrophile

3. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 3 16.1 Bromination of Aromatic Rings Benzene’s  electrons participate as a Lewis base in reactions with Lewis acids The product is formed by loss of a proton, which is replaced by bromine FeBr 3 is added as a catalyst to polarize the bromine reagent

4. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 4 Addition Intermediate in Bromination The addition of bromine occurs in two steps In the first step the  electrons act as a nucleophile toward Br 2 (in a complex with FeBr 3 ) This forms a cationic addition intermediate from benzene and a bromine cation The intermediate is not aromatic and therefore high in energy (see Figure 16.2)

5. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 5 Formation of Product from Intermediate The cationic addition intermediate transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) This restores aromaticity (in contrast with addition in alkenes)

6. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 6 16.2 Other Aromatic Substitutions The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate George Willard Wheland 1907-1974

7. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 7 Aromatic Chlorination and Iodination Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution with the addition of other reagents to promote the reaction Chlorination requires FeCl 3 Iodine must be oxidized to form a more powerful I + species (with Cu + or peroxide)

8. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 8 Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO 2 + (nitronium ion) The reaction with benzene produces nitrobenzene

9. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 9 Aromatic Sulfonation Substitution of H by SO 3 (sulfonation) Reaction with a mixture of sulfuric acid and SO 3 Reactive species is sulfur trioxide or its conjugate acid Reaction occurs via Wheland intermediate and is reversible

10. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 10 Alkali Fusion of Aromatic Sulfonic Acids Sulfonic acids are useful as intermediates Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO 3 H group with an OH Example is the synthesis of p-cresol

11. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 11 16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Aromatic substitution of a R + for H Aluminum chloride promotes the formation of the carbocation Wheland intermediate forms

12. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 12 Limitations of the Friedel-Crafts Alkylation Only alkyl halides can be used (F, Cl, I, Br) Aryl halides and vinylic halides do not react (their carbocations are too hard to form) Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group

13. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 13 Control Problems Multiple alkylations can occur because the first alkylation is activating

14. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 14 Carbocation Rearrangements During Alkylation Similar to those that occur during electrophilic additions to alkenes Can involve H or alkyl shifts

15. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 15 16.4 Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl 3 introduces acyl group,  COR Benzene with acetyl chloride yields acetophenone

16. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 16 Mechanism of Friedel-Crafts Acylation Similar to alkylation Reactive electrophile: resonance-stabilized acyl cation An acyl cation does not rearrange

17. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 17 16.5 Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much) less reactive than benzene Substituents affect the orientation of the reaction – the positional relationship is controlled ortho- and para-directing activators, ortho- and para- directing deactivators, and meta-directing deactivators

18. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 18 Origins of Substituent Effects An interplay of inductive effects and resonance effects Inductive effect - withdrawal or donation of electrons through a  bond Resonance effect - withdrawal or donation of electrons through a  bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring

19. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 19 Inductive Effects Controlled by electronegativity and the polarity of bonds in functional groups Halogens, C=O, CN, and NO 2 withdraw electrons through  bond connected to ring Alkyl groups donate electrons

20. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 20 Resonance Effects – Electron Withdrawal C=O, CN, NO 2 substituents withdraw electrons from the aromatic ring by resonance  electrons flow from the rings to the substituents

21. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 21 Resonance Effects – Electron Donation Halogen, OH, alkoxyl (OR), and amino substituents donate electrons  electrons flow from the substituents to the ring Effect is greatest at ortho and para

22. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 22 Contrasting Effects Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring Resonance interactions are generally weaker, affecting orientation The strongest effects dominate

23. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 23 16.6 An Explanation of Substituent Effects Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation) Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate

24. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 24 Ortho- and Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselves Alkyl group is most effective in the ortho and para positions

25. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 25 Ortho- and Para-Directing Activators: OH and NH 2 Alkoxyl, and amino groups have a strong, electron- donating resonance effect Most pronounced at the ortho and para positions

26. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 26 Ortho- and Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate

27. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 27 Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation from carbocation intermediate Resonance cannot produce stabilization

28. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 28 Summary Table: Effect of Substituents in Aromatic Substitution

29. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 29 16.7 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive

30. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 30 Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome Usually gives mixtures of products

31. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 31 Meta-Disubstituted Compounds Are Unreactive The reaction site is too hindered To make aromatic rings with three adjacent substituents, it is best to start with an ortho- disubstituted compound

32. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 32 16.8 Nucleophilic Aromatic Substitution Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles Form addition intermediate (Meisenheimer complex) that is stabilized by electron- withdrawal Halide ion is lost to give aromatic ring

33. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 33 16.9 Benzyne Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure The reaction involves an elimination reaction that gives a triple bond The intermediate is called benzyne

34. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 34 Evidence for Benzyne as an Intermediate Bromobenzene with 14 C only at C1 gives substitution product with label scrambled between C1 and C2 Reaction proceeds through a symmetrical intermediate in which C1 and C2 are equivalent— must be benzyne

35. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 35 Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp 2 -hybridized carbons, not the usual sp The triple bond has one  bond formed by p–p overlap and by weak sp 2 –sp 2 overlap

36. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 36 16.10 Oxidation of Aromatic Compounds Alkyl side chains can be oxidized to  CO 2 H by strong reagents such as KMnO 4 and Na 2 Cr 2 O 7 if they have a C-H next to the ring Converts an alkylbenzene into a benzoic acid, Ar  R  Ar  CO 2 H

37. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 37 Bromination of Alkylbenzene Side Chains Reaction of an alkylbenzene with N-bromo- succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

38. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 38 Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical Reacts with Br 2 to yield product Br· radical cycles back into reaction to carry chain Br 2 produced from reaction of HBr with NBS

39. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 39 16.11 Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts)

40. Chapter 1740 Birch Reduction This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene. The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol.

41. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 41 Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reduction Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst Clemmensen Reduction

42. McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003 42 16.12 Synthesis Strategies These syntheses require planning and consideration of alternative routes Work through the practice problems in this section following the general guidelines for synthesis (and retrosynthetic analysis in 8.10)