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16. Chemistry of Benzene: Electrophilic Aromatic Substitution

16. Chemistry of Benzene: Electrophilic Aromatic Substitution. Benzene is aromatic: a cyclic conjugated compound with 6  electrons Reactions of benzene lead to the retention of the aromatic core. Substitution Reactions of Benzene and Its Derivatives.

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16. Chemistry of Benzene: Electrophilic Aromatic Substitution

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  1. 16. Chemistry of Benzene: Electrophilic Aromatic Substitution

  2. Benzene is aromatic: a cyclic conjugated compound with 6  electrons Reactions of benzene lead to the retention of the aromatic core Substitution Reactions of Benzene and Its Derivatives

  3. Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactions Examine relationship between aromatic structure and reactivity Relationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized Why this Chapter?

  4. 16.1 Electrophilic Aromatic Substitution Reactions (EAS): • Reactions typical of addition to alkenes do not work on aromatic double bonds. • Need more electrophilic (more positive) halogen in order to break an aromatic double bond.

  5. EAS: Bromination EAS occurs in two steps: Addition followed by Elimination • FeBr3 acts as a catalyst to polarize the bromine reagent and so make it more positive (more electrophilic) • The  electrons of the aromatic ring act as a nucleophile toward the now more electrophilic Br2(in the FeBr3 complex) Addition The cationic addition intermediate is called a sigma complex

  6. EAS: Bromination EAS occurs in two steps: Addition followed by Elimination • The cationic addition intermediate (sigma complex) transfers a proton to FeBr4-(from Br- and FeBr3) • Aromaticity is restored • (in contrast with addition in alkenes which is not followed by elimination) Addition Elimination

  7. EAS: Bromination EAS occurs in two steps: Addition followed by Elimination • The cationic addition intermediate (sigma complex) transfers a proton to FeBr4-(from Br- and FeBr3) • Aromaticity is restored • (in contrast with addition in alkenes which is not followed by elimination) Elimination is driven by the stability of becoming aromatic

  8. 16.2 Other Aromatic Substitutions • Chlorine and iodine(but not fluorine, which is too reactive) can produce aromatic substitution products Chlorination requires FeCl3 Iodine must be oxidized (with Cu+ or peroxide) to form a more powerful I+ species

  9. Example: A common Amino Acid

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

  11. Reduction of Nitration Product: • To put an amino (NH2) group on an aromatic ring • first Nitrate • then reduce

  12. Aromatic Sulfonation • Substitution of H by SO3 (sulfonation) with a mixture of sulfuric acid and SO3 • Reactive species is sulfur trioxide or its conjugate acid • Reaction is Reversible: • Can remove sulfonyl group with H+,H2O, heat

  13. Aromatic Hydroxylation • Hard to directly add –OH to an aromatic ring in lab. Formation of Electrophile

  14. Aromatic Hydroxylation • Biological systems use Enzymes to hydroxylate aromatics

  15. 16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Electrophilic C+ forms • Alkylation (substitution of Carbon compounds) among most useful electrophilic aromatic subsitution reactions • Aromatic substitution of R+ for H+ • Aluminum chloride promotes the formation of the carbocation Addition Elimination

  16. Friedel-Crafts Alkylation: Limitations • Only alkyl halides can be used (F, Cl, I, Br) • Aryl halides (Ar-X) and vinylic halides (CH2=CH-X) 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

  17. Friedel-Crafts Alkylation: Control Problems • Multiple alkylationscan occur because the first alkylation is activating (makes aromatic ring more nucleophilic so more likely to add again)

  18. Friedel-Crafts Alkylation: Control Problems Carbocation Rearrangements • Similar to those that occur during electrophilic additions to alkenes • Can involve H or alkyl shifts

  19. Example:

  20. Friedel-Crafts Acylation • 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

  21. Friedel-Crafts Acylation: Mechanism • Similar to alkylation • Reactive electrophile: resonance-stabilized acyl cation • An acyl cation does not rearrange Electrophilic C+ forms = Acylium ion Addition Elimination

  22. EAS: Summary

  23. 16.4 Substituent Effects • Substituents that donate electrons make ring more nucleophilic • Electron donating groups (edg) activate the ring toward EAS • Substitutients that withdraw electrons make less nucleophilic • Electron withdrawing groups (ewg) deactivate the ring toward EAS Nucleophile Electrophile

  24. Substituent Effects • Substituents influence by induction edg activate the ring toward EAS ewg deactivate the ring toward EAS Halogens, C=O, CN, and NO2withdraw electrons through s bond connected to ring Alkyl groups donate electrons

  25. Substituent Effects • Substituents influence by resonance Halogen, OH, alkoxyl (OR), and amino substituentsdonate electrons edg activate the ring toward EAS

  26. Substituent Effects • Substituents influence by resonance C=O, CN, NO2substituentswithdraw electrons from the aromatic ring by resonance ewg deactivate the ring toward EAS

  27. Substituent Effects • Substituents influence by resonance edgsput negative character at o- and p- positions (make o- and p- positions morenucleophilic) Direct incoming electrophile into o- or p- spots ewgsput positive character at o-andp- positions (make o- and p- positions lessnucleophilic) Direct incoming electrophile into m- spots

  28. 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

  29. 16.5 Ortho- & 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

  30. Ortho- and Para-Directing Activators: OH and NH2 • Alkoxyl, and amino groups have a strong, electron-donating resonance effect Most pronounced at the ortho and para positions

  31. Ortho- & 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

  32. Meta-Directing Deactivators • Inductive and resonance effects reinforce each other • Ortho and para intermediates destabilized by deactivation of carbocation intermediate Resonance cannot produce stabilization

  33. Summary:

  34. Another Summary:

  35. 16.6 Trisubstituted Benzenes: Additivity of Effects • If the directing effects of the two groups are the same, the result is additive

  36. Learning Check: Br2, FeBr3 ?

  37. Solution: Br2, FeBr3 ?

  38. 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

  39. Meta-Disubstituted Compounds • The reaction site is too hindered • To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

  40. 16.7 Nucleophilic Aromatic Substitution Aryl halides with ewg’s o- and p- react with nucleophiles Sanger’s reagent: For labeling proteins in biochemistry

  41. Nucleophilic Aromatic Substitution

  42. Nucleophilic Aromatic Substitution

  43. Nucleophilic Aromatic Substitution ewg’s o- and p- stabilize the intermediate Intermediate Meisenheimer complex is stabilized by electron-withdrawal Halide ion is lost to give aromatic ring

  44. 16.8 Benzyne • Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure Elimination reaction gives a triple bond intermediate called benzyne

  45. Evidence for Benzyne • 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 & C2 are equivalent— must be benzyne

  46. 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 another by weak sp2–sp2 overlap

  47. 16.9 Benzylic Oxidation • Alkyl side chains with a C-H next to the ring can be oxidized to CO2H by strong reagents such as • KMnO4 and • Na2Cr2O7 • O2, Co(III) • Converts an alkylbenzene into a benzoic acid, • ArR ArCO2H

  48. Examples:

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