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CHAPTER 15

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  1. CHAPTER 15 Reactions Involving Aromatic Compounds

  2. Chapter 15 • Section 1— Electrophilic Aromatic Substitution Reactions • Section 2— A General Mechanism for Electrophilic Aromatic Substitution: Arenium Ions • Section 3— Halogenation of Benzene • Section 4— Nitration of Benzene • Section 5— Sulfonation of Benzene • Section 6— Friedel-Crafts Alkylation • Section 7— Friedel-Crafts Acylation • Section 8— Limitations of Friedel-Crafts Reactions • Section 9— Synthetic Applications of Friedel=-Crafts Acylations: The Clemmensen Reduction

  3. Chapter 15 • Section 10— Effect of Substituents on Reactivity and Orientation • Section 11— Theory of Substituent Effects on Electrophilic Aromatic Subititution • Section 12— Reactions of the Side Chain of Alkylbenzenes • Section 13— Alkenylbenzenes • Section 14— Synthetic Applications • Section 15— Allylic and Benzylic Halides in Nucleophilic Substitution Reactions • Section 16— Reduction of Aromatic Compounds

  4. Reactions of Aromatic Compounds • Benzenoid hydrocarbons are often called arenes. The symbol used to represent the aryl group

  5. Electrophilic Aromatic Substitution • This most characteristic reaction of arenes may be used to introduce a variety of substitutents into the structure: • Note: In these reactions, an electrophile substitutes for an H on the aromatic ring. This substitution contrasts with the addition of an electrophile to an alkene. In addition to an alkene, the weaker π-bond is replaced by stronger σ-bonds, but this does not occur with an arene because the large stabilizing resonance energy of the aromatic ring would be lost.

  6. Examples of Electrophilic Aromatic Substitution Reactions • These reactions are commonly used synthetic procedures for modifying arenes. They proceed by a general mechanism initiated by addition of an electrophile E+ to the aromaticπ-system, forming a nonaromatic carbocation intermediate called an arenium ion.

  7. Description of Mechanism Using Resonance Structures • Step 1: Attack by the Electrophile • Twoπ-electrons form a σ-bond to the incoming electrophile yielding a delocalized carbocation intermediate called an arenium ion. These resonance structures show the distribution of positive charge in the arenium ion. The arenium ion is non-aromatic, but it is reasonably stable because of charge dispersal over the carbons ortho and para to the site of attachment of the electrophile.

  8. Step 2: Deprotonation of the Arenium Ion and Re-aromatization The Lewis base that attacks and removes the proton may, as shown, be the conjugate base of the electrophile or some other Lewis base that may be present.

  9. Free-Energy Diagram for anElectrophilic Aromatic Substitution Reaction • The much larger energy of activation requirement for Step 1 makes it the slow, rate-determining step.

  10. The Arenium Ion Intermediate • A calculated structure for the resonance-stabilized (but non-aromatic) arenium ion intermediate, a delocalized cyclohexadienyl cation, is shown on the right. The blue coloration at the para and the two ortho carbons, suggesting low electron densities there, is in line with the partial positive charge locations in the resonance hybrid shown on the left above.

  11. Halogenation of Benzene • Halogenation of benzene and other arenes is one of the most common ways to functionalize aromatics. The reaction of benzene with Cl2 or Br2 requires catalysis by a Lewis acid. (Benzene, in contrast to alkenes, will not decolorize a solution of Br2 in CCl4.) • Commonly employed Lewis acids are the iron halides, preformed or generated in situ:

  12. Role of the Catalyst • The Lewis acid complexes with and polarizes the X2 producing a more reactive electrophile capable of disrupting the rather stable aromatic π-system in benzene and other arenes. • The complex transfers a positive bromide ion to theπ-system of the arene. The effective electrophile in the bromination reaction is sometimes written as Br+, formed as shown below, but direct involvement of the complex is more likely.

  13. Mechanism: • Step 1: Electrophilic Attack • Step 2: Deprotonation and Re-aromatization

  14. Chlorination of Benzene • Chlorination of benzene proceeds by a mechanism parallel with that for bromination, a complex of FeCl3 and Cl2 providing the effective electrophile [Cl+]. Fluorination of Benzene • Direct reaction of F2 with benzene is very exothermic and proceeds explosively. Special procedures are required to carry out this reaction safely. • Fluorobenzene and other monofluoroarenes may be synthesized indirectly by way of aryl diazonium ions, which will be considered later.

  15. Iodination of Benzene • Direct iodination of benzene with I2 is a very slow reaction because of the unfavorable bond energy changes, but it can be achieved in the presence of an oxidizing agent. • Alternatively, iodobenzene and other iodoarenes may be prepared indirectly by way of aryl diazonium ions. Reactivity in the Halogenation of Benzene Fluorination>Chlorination>Bromination>Iodination Explosively reactiveVery slow

  16. Nitration of Benzene • Benzene reacts only slowly with hot concentrated nitric acid to give nitrobenzene. The reaction is much faster in a mixture of concentrated nitric acid (pKa=-1.4) and concentrated sulfuric acid, a much stronger acid (pKa=-9).

  17. Mechanism of Nitration (1)Generation of the Electrophile Nitric acid undergoes reversible dehydration in the presence of concentrated sulfuric acid producing the nitronium ion, a strong electrophile.

  18. (2)Electrophilic Attack (3) Deprotonation and Re-aromatization

  19. Sulfonation of Benzene • Benzene reacts with fuming sulfuric acid (concentrated sulfuric acid plus added SO3, the actual electrophile) to give benzenesulfonic acid. • In concentrated sulfuric acid alone, an equilibrium-limited supply of SO3 effects slow sulfonation. (1) Generation of the Electrophile

  20. (2) Electrophilic Attack (3) Deprotonation and Re-aromatization

  21. (4) Acid-Base Equilibrium Synthetic Applications • Although introduction of a sulfonic acid group is generally of more limited interest than other electrophilic substitution reactions, the reversibility of sulfonation leads to its use in synthetic strategy. Heating arylsulfonic acids in dilute sulfuric acid removes the sulfonic acid function.

  22. Friedel-Crafts Alkylation • Discovered in 1877 by French chemist Charies Friedel and his American collaborator James Crafts, this alkylation reaction (one introducing an alkyl group) and the related acylation reaction (one introducing an acyl group) are among the most useful synthetic reactions. Alkylation of an Arene • This reaction requires a Lewis acid catalyst, typically aluminum chloride, AlCl3. Many variations of the Friedel-Crafts alkylation reaction have been developed. All proceed by similar mechanisms.

  23. A Mechanism for the Alkylation Reaction • The Lewis acid catalysts generally required in Friedel-Crafts reactions promote formation of strong electrophiles. (1)Generation of the Electrophile • With 10 halides, the complex itself, acting as an R+ transfer agent, reacts with the arene. • With 20 and 30 alkyl halides, dissociation to carbocation intermediates seems to occur, and the resulting R+ species react with the arene.

  24. (2) Electrophilic Attack (3) Deprotonation and Re-aromatization

  25. Evidence for Carbocation Intermediates • Skeletal rearrangement is observed in Friedel-Crafts alkylation reactions when concurrent change to a more stable carbocation can occur. • It is believed rearrangement occurs during reversible dissociation to a short-lived carbocation:

  26. Other Alkylation Methods • Any reaction that produces carbocations (or carbocation-like intermediates) may be used to alkylate benzene and other arenes. Examples 1) Alkenesalkylate arenes in the presence of strong acids:

  27. 2) Alcoholsalkylate arenes in the presence of strong acids:

  28. Friedel-Crafts Acylation • Acylation is the introduction of an acyl group, R-C-, into a structure. • The Friedel-Crafts acylation reaction attaches an acyl group to an arene. A Lewis acid catalyst is required to generate the electrophile from an acyl halide reactant.

  29. Preparation of Acid (or Acyl) Chlorides • Acid chlorides are readily prepared from the corresponding carboxylic acids with thionyl chloride (SOCl2) or phosphorus pentachloride (PCl5). Examples

  30. A Mechanism for Friedel-Crafts Acylation • Generation of the Electrophile • Acylium ions are generally thought to be the electronphilic intermediates in Friedel-Crafts acylation reactions. As shown, these ions have two contributing resonance structures.

  31. (2) Electrophilic Attack (3) Deprotonation and Re-aromatization

  32. Complexation of the Ketone Product • The ketone forms a Lewis complex with the AlCl3 that persists in the Reaction mixture until the work up with water. Accordingly, one full equivalent of AlCl3 is required for the reaction. • This complexation deactivates the aromatic ring towards further electrophilic attack (discussed later), so only monsubstitution occurs.

  33. Limitations of the Friedel-Crafts Reactions (1) Rearrangments during Alkylations Whenever carbocation intermediates are formed, they are subject to rearrangements that produce more stable species. Example: • During the Friedel-Crafts reaction of benzene with butyl bromide a 1,2-hydride shift, possibly concurrent with dissociation, produces some of the more stable sec-butyl carbocation. A mixtur e of products results.

  34. (2) Friedel-Crafts reactions do not proceed well with electron-deficient benzenes, or with aromatics that have amino groups. • The following electron-withdrawing substitutents lead to electron- deficient π-systems that react slowly with electrophiles. • In general, Friedel-Crafts reactions do not proceed with benzenes that have these substituent groups (which are meta-directing; discussed later). • Benzenes with amino functions (-NR2) do not undergo Friedel-Crafts reactions because they rapidly react with the Lewis acid catalysts to produce an unreactive complex salt.

  35. (3) Aryl and vinylic halides cannot be used as the halide because they do not form carbocations readily. (4) Polyalkylations often occur because the alkylbenzene products are more reactive than benzene in electrophilic substitution reactions.

  36. Polyalkylation is not a problem because the acyl group (RC-) is electron-withdrawing, which deactivates the aromatic ring towards furtherelectrophilic addition. Complexing of the carbonyl with AlCl3 further reduces π-electron density in the ring.

  37. Synthetic Applications of Friedel-Crafts Acylation:The Clemmensen Reduction • Acylation is often the preferred way to introduce a side-chain onto a benzene ring because rearrangements and polysubstitution do not occur. • Example: In the synthesis of propylbenzene by alklation, rearrangement affords a mixture of it and its isopropyl isomer. Polysubstitution will also be a complication. These problems can be avoided by use of acylation followed by reduction. • Reduction of the ketone to an alkyl group may be accomplished by any of several standard methods.

  38. The Clemmensen Reduction • In 1913, E. Clemmensen developed a standard reduction that involves refluxing the ketone in a heterogeneous mixture of amalgamated zinc and hydrochloric acid. Often, acetic acid is added to improve the solubility of the ketone. Good yields of the alkylbenzene are typically obtained.

  39. Acid Anhydrides in the Friedel-Crafts Acylation Reaction • Acid anhydrides are alternatives to acid chlorides in the Friedel-Crafts acylation reaction, as illustrated below. Example: The Friedel-Crafts Reaction of Benzene and Acetic Anhydride

  40. The acid anhydride acts as a “pseudo acid chloride” in many reactions because the carboxylate leaving group mimics the chloride leaving group. In the Friedel-Crafts reaction, complexation with the AlCl3 promotes bond cleavage and formation of an acylium ion intermediate. • After formation of the acylium ion, the acylation reaction proceeds bythe usual mechanism. During the work up with water, the aluminate salt is hydrolyzed to produce an equivalent of the carboxylic acid.

  41. Friedel-Crafts Syntheses with Cyclic Anhydrides • Cyclic anhydrides are starting points for a multi-step synthesis of carboxylic acids.

  42. Substituent Effects on the Reactivity and Orientationof Electrophilic Aromatic Substitution • Substituent groups already on the benzene ring greatly influence both the reactivity of electrophilic attack, and the site (ortho, meta, or para) of attachment of the incoming electrophile. Classification of Substituents • Substituents are classified as activating or deactivating relative to the reactivity of benzene. • Substituents also are classified as orth/para directing (o/p directing) or meta directing (m directing). There is a fundamental theoretical connection between the reactivity influence and site direction of a substituent group.

  43. Activating Groups: Ortho-Para Directors The methyl and other alkyl groups are in this category. Example: Nitration of toluene proceeds faster than that of benzene and gives predominantly ortho and para nitrotoluene products. • Alkyl groups are also activating and ortho/para directing in other electrophilic aromatic substitutions. Additional Activating and Ortho/Para Directing Groups

  44. Deactivating Groups: Meta Directors • The nitro group, -NO2, is an example. • Nitration of nitrobenzene proceeds at a rate approximately 10-8 times the rate of nitration of benzene, and the major product is m-dinitrobenzene. Other deactivating and meta-directing groups are:

  45. Halogen Substituents: Deactivating but Ortho/Para Directing • Chloro and bromo substituents are unique in decreasing reactivity in electrophilic aromatic substitution but producing mostly ortho and para products.

  46. Summary of Substituent Effects onElectrophilic Aromatic Substitution

  47. Theory of Substituent Effects • The reactivity of substituted benzenes in electrophilic aromatic substitution is determined by the electronic influence of the substituent on the developing carbocation intermediate, the arenium ion. • Illustration: An electrophile attacks o, m, or p to a substituent, Q. • When Q is electron-releasing, it stabilizes the arenium ion intermediate, decreasing the energy of the transition state relative to that from benzene. • When Q is electron-withdrawing, it destabilizes the arenium ion ntermediate, increasing the energy of the transition state relative to that from benzene.

  48. Comparison of the Rate Determining Step for Benzene andSubstituted Benzenes in Electrophilic Aromatic Substitution • The major electronic effect of the substiuent (electron-withdrawing or electron-donating) is on the transition state energy, which is lowered as the ring electron density increases.

  49. Since the addition of the electrophile is the rate determing step (RDS), the reactivities of the arenes are in the order:

  50. The Inductive Effect • The inductive effect of a substituent Q arises from electrostatic interactions transmitted through polarized sigma bonds. • In a covalent bond where Q is more electronegative than C, there is a permanent polarization of the sigma electrons toward the more electronegative atom (e.g., a halogen atom): • Thus the ring carbon with the substituent is more electropositive than the other carbons in the ring. • Other examples of electron withdrawing substituents are these, in which an atom attached to the ring has a full or partial positive charge: