1. Chapter 18 Reactions of Aromatic molecules
Benzene is aromatic: a cyclic conjugated compound with 6  electrons
Reactions of benzene lead to the retention of the aromatic core

2. Types of Reactions Electrophilic substitution Diazonium chemistry
Nucleophilic substitution
Misc. modification of substituents

3. Electrophilic Substitution Reactions of Benzene and Its Derivatives

4. Electrophilic Substitution versus addition
Arenium ion: Wheland intermediate
Also called sigma complex

5. Energy diagram comparison of electrophilic substitution versus electrophilic addition
Is this kinetic or thermodynamic control?

6. Electrophilic Bromination of Aromatic Rings
toluene
para-bromotoluene
ortho-bromotoluene
meta-bromonitrobenzene
Regiochemistry (ortho, para, meta) will depend on relative stability of resonance structures for carbocation intermediates

7. Mechanism for Electrophilic Bromination of Aromatic Rings
para carbocation
ortho carbocation
ortho carbocation

9. Electrophilic substitution of Bromobenzene

10. Halogens are ortho para directors, but are still deactivating compared with benzene

11. Transformations of Aryl bromides

12. Aromatic Nitration
The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion)
The reaction with benzene produces nitrobenzene
Gun solvent

13. Nitration of toluene: an electron rich monomer

14. ortho & para Regioselectivity explained
Kinetics are more favorable for ortho and para isomers with electron donating substitutent on benzene

17. High explosive: Shock wave
Too corrosive for artillery shells
High explosive: Shock wave
Secondary explosive: requires primer (primary explosive) to detonate
Nitroaromatics are harmful: aplastic anemia and liver toxicity

18. Reactions of nitroaromatics
Nitro is deactivating (destabilizes the Wheland intermediate & slows reactions).
Reactions are 100,000 slower than with benzene
Meta directing
More polynitration
mono-bromination
Reduction to anilines and azo compounds
Nucleophilic aromatic substitution

19. Meta selective: electron withdrawing groups
electron withdrawing group inductively destabilizes adjacent carbocations in ortho and para cases.
No adjacent carbocation in meta regiochemistry resonance structures

20. Reduction of Nitroaromatics to Aryl amines
Amine group is electron donating: changes subsequent regiochemistry from meta to ortho-para

21. Aromatic Sulfonation Substitution of H by SO3 (sulfonation)
Reaction with a mixture of sulfuric acid and SO3
Reactive species is sulfur trioxide or its conjugate acid
Reaction occurs via Wheland intermediate and is reversible

22. 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 SO3H group with an OH
Example is the synthesis of p-cresol

23. Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
Aromatic substitution of a R+ for H
Aluminum chloride promotes the formation of the carbocation
Rearrangement of carbocation can occur

24. Friedel Craft alkylation mechanism

25. Friedel Craft alkylation with rearrangements

26. 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

27. Control Problems
Multiple alkylations can occur because the first alkylation is activating

28. Acylation of Aromatic Rings
Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR
Benzene with acetyl chloride yields acetophenone

29. Friedel Craft Acylation Mechanism

30. Acylation – No rearrangement of acylium ions

32. 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

33. Strongly Activating o,p directors: Multiple additions

34. Reduce reactivity with acetyl groups

35. Summary of activation versus deactivation
and ortho & para versus meta direction

36. With multiple substitutents there can be antagonistic or reinforcing effects
Antagonistic or Non-Cooperative
Reinforcing or Cooperative
D = Electron Donating Group (ortho/para-directing)
W = Electron Withdrawing Group (meta-directing)

37. Multiple Substituents in antagonistic systems
The most strongly activating substituent will determine the position of the next substitution. May have mixtures.
=>

39. Sulfonic acid blocking groups

41. ?

42. ?

44. Electrophilic substitution reaction used to make plastics
Acid or base catalyzed reactions
Bakelite, Novolac
Acid catalyzed reaction of phenol with formaldehyde

45. Electrophilic substitution reaction used to make plastics
Acid catalyzed reaction of phenol with formaldehyde

46. Electrophilic substitution reaction used to make plastics
Base catalyzed reaction of phenol with formaldehyde

47. Nucleophilic Aromatic Substitution
While protons attached to electron-rich aromatics can be displaced by electrophiles, halogens attached to electron-depleted aromatics can be displaced by nucleophies
Nucleophilic aromatic substitution is similar to SN1/SN2 in its outcome, but follows completely different mechanisms
Substitution Nucleophilic Aromatic (SNAr), the Benzyne Mech, and reaction of diazonium salts

48. SNAr Mechanism: Electron EWG’s

49. Addition-Elimination Reactions
Typical for aryl halides with nitro groups in ortho or para position
Addition to form intermediates (Meisenheimer complexes) by electron-withdrawal
Halide ion is then lost by elimination

50. Chlorobenzene is unreactive under ordinary laboratory conditions…

51. …but brute force will do the job!
However, this can’t be the same mechanism

52. Nucleophilic substitution aromatic
Strong EWG ortho or para to leaving group (F, Cl, Br, I, OTf)
Strong nucleophile (HO-, RO-, Amide, thiolate, carbanions)

53. SNAr used in making polymers (plastics)

54. Elimination-Addition: Benzynes
The reaction involves an elimination reaction that gives a triple bond, followed by rapid addition of water
The intermediate is called benzyne

55. Evidence for Benzyne as an Intermediate
Bromobenzene with 14C 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

56. Structure of Benzyne Benzyne is a highly distorted alkyne
The triple bond uses sp2-hybridized carbons, not the usual sp
The triple bond has one  bond formed by p–p overlap and by weak sp2–sp2 overlap

59. Another Nucleophilic Like reaction using
Diazonium Salts (made from Anilines)
ArNH2 is easily made from reduction of nitrobenzenes. Permits preparation of molecules impossible to make otherwise

60. Mechanism for formation of Diazonium Salts from Anilines

61. Three possible reaction mechanisms for Nucleophilic substitution reactions with Diazonium salts
Thermal ionization (like SN1)
e.g. Formation of phenol
Redox (radical intermediate)
Organometallic
e.g. Sandmeyer reaction

62. Diazonium chemistry

63. 16.10 Oxidation of Aromatic Compounds
Alkyl side chains can be oxidized to CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring
Converts an alkylbenzene into a benzoic acid, ArR  ArCO2H

65. 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

66. Mechanism of NBS (Radical) Reaction
Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical
Reacts with Br2 to yield product
Br· radical cycles back into reaction to carry chain
Br2 produced from reaction of HBr with NBS

67. 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)

69. Summary of reactions not involving aromatic substitution
Reduction of nitrobenzenes to anilines
Conversion of benzenesulfonic acids to phenols
Side chain oxidation of alkylbenzenes to benzoic acids
Side chain halogenation of alkylbenzenes
Reduction of benzenes to cyclohexanes
Reduction of aryl ketones to alkyl benzenes