Spring 2009Dr. Halligan CHM 236 Electrophilic Aromatic Substitution Chapter 18

2 Background The characteristic reaction of benzene is electrophilic aromatic substitution (EAS)—a hydrogen atom is replaced by an electrophile.

3 Background Why doesn’t benzene undergo typical addition reactions? Electrophilic Aromatic Substitution of a hydrogen keeps the aromatic ring intact.

4 Figure 18.1 Five examples of electrophilic aromatic substitution

5 Background All EAS reactions occur by the same mechanism. 1.Make the electrophile (E + ). 2.Attack the electrophile (E + ). 3.Re-aromatize the ring.

6 Background After formation of the E +, the next step in the EAS mechanism forms a carbocation, for which three resonance structures can be drawn.

7 Background The energy changes in electrophilic aromatic substitution are shown below: Figure 18.2 Energy diagram for electrophilic aromatic substitution: PhH + E + → PhE + H +

8 Halogenation In halogenation, benzene reacts with Cl 2 or Br 2 in the presence of a Lewis acid catalyst, such as FeCl 3 or FeBr 3, to give the aryl halides chlorobenzene or bromobenzene respectively. Analogous reactions with I 2 and F 2 are not synthetically useful because I 2 is too unreactive and F 2 reacts too violently.

9 Halogenation Chlorination proceeds by a similar mechanism.

10 Halogenation Figure 18.3 Examples of biologically active aryl chlorides

11 Nitration and Sulfonation Nitration and sulfonation introduce two different functional groups into the aromatic ring. Nitration is especially useful because the nitro group can be reduced to an NH 2 group.

12 Nitration and Sulfonation Generation of the electrophile in nitration requires strong acid (H 2 SO 4 ).

13 Nitration and Sulfonation Generation of the electrophile in sulfonation requires strong acid (H 2 SO 4 ).

14 Friedel-Crafts Alkylation and Friedel-Crafts Acylation In Friedel-Crafts alkylation, treatment of benzene with an alkyl halide and a Lewis acid (AlCl 3 ) forms an alkyl benzene.

15 Friedel-Crafts Alkylation and Friedel-Crafts Acylation In Friedel-Crafts acylation, a benzene ring is treated with an acid chloride (RCOCl) and AlCl 3 to form a ketone. Because the new group bonded to the benzene ring is called an acyl group, the transfer of an acyl group from one atom to another is an acylation.

16 Friedel-Crafts Alkylation and Friedel-Crafts Acylation

17 Friedel-Crafts Alkylation and Friedel-Crafts Acylation

18 Friedel-Crafts Alkylation and Friedel-Crafts Acylation In Friedel-Crafts acylation, the Lewis acid AlCl 3 ionizes the carbon- halogen bond of the acid chloride, thus forming a positively charged carbon electrophile called an acylium ion, which is resonance stabilized. The positively charged carbon atom of the acylium ion then goes on to react with benzene in the two step mechanism of electrophilic aromatic substitution.

19 Friedel-Crafts Acylation of Benzene Charles Friedel and James Crafts discovered the Friedel-Crafts “acyl” and “alkylation” reactions in In the first reaction, an acyl group reacts with a catalyst to form an acylium ion electrophile. Then the electrophile gets attacked by the benzene ring and after an aqueous work-up procedure, the acylated benzene derivative is isolated.

20 Friedel-Crafts Alkylation and Friedel-Crafts Acylation Three additional facts about Friedel-Crafts alkylation should be kept in mind. [1]Vinyl halides and aryl halides do not react in Friedel- Crafts alkylation.

21 Friedel-Crafts Alkylation and Friedel-Crafts Acylation [2]Rearrangements can occur. These results can be explained by carbocation rearrangements.

22 Friedel-Crafts Alkylation and Friedel-Crafts Acylation

23 Friedel-Crafts Alkylation and Friedel-Crafts Acylation Rearrangements can occur even when no free carbocation is formed initially.

24 Friedel-Crafts Alkylation and Friedel-Crafts Acylation [3]Other functional groups that form carbocations can also be used as starting materials.

25 Friedel-Crafts Alkylation and Friedel-Crafts Acylation Each carbocation can then go on to react with benzene to form a product of electrophilic aromatic substitution. For example:

26 Alkylation of Benzene by Acylation-Reduction There is a better way to make alkylbenzene derivatives containing straight-chain alkyl groups. In this method, a Friedel-Crafts acylation is done first and then reduction of the carbonyl moiety with H 2 /Pd provides the desired alkyl-substituted benzene.

27 Friedel-Crafts Alkylation and Friedel-Crafts Acylation Starting materials that contain both a benzene ring and an electrophile are capable of intramolecular Friedel-Crafts reactions.

28 Friedel-Crafts Alkylation and Friedel-Crafts Acylation Figure 18.4 Intramolecular Friedel-Crafts acylation in the synthesis of LSD

29 Substituted Benzenes Many substituted benzene rings undergo EAS reactions. Each substituent either increases or decreases the electron density in the benzene ring, and this affects the course of EAS reaction.

30 Substituted Benzenes Considering inductive effects only, the NH 2 group withdraws electron density and CH 3 donates electron density.

31 Substituted Benzenes Resonance effects are only observed with substituents containing lone pairs or  bonds. An electron-donating resonance effect is observed whenever an atom Z having a lone pair of electrons is directly bonded to a benzene ring.

32 Substituted Benzenes An electron-withdrawing resonance effect is observed in substituted benzenes having the general structure C 6 H 5 -Y=Z, where Z is more electronegative than Y. Seven resonance structures can be drawn for benzaldehyde (C 6 H 5 CHO). Because three of them place a positive charge on a carbon atom of the benzene ring, the CHO group withdraws electrons from the benzene ring by a resonance effect.

33 Substituted Benzenes To predict whether a substituted benzene is more or less electron rich than benzene itself, we must consider the net balance of both the inductive and resonance effects. For example, alkyl groups donate electrons by an inductive effect, but they have no resonance effect because they lack nonbonded electron pairs or  bonds. Thus, any alkyl-substituted benzene is more electron rich than benzene itself.

34 Substituted Benzenes The inductive and resonance effects in compounds having the general structure C 6 H 5 -Y=Z (with Z more electronegative than Y) are both electron withdrawing.

35 Substituted Benzenes These compounds represent examples of the general structural features in electron-donating and electron withdrawing substituents.

36 Electrophilic Aromatic Substitution and Substituted Benzenes Electrophilic aromatic substitution is a general reaction of all aromatic compounds, including polycyclic aromatic hydrocarbons, heterocycles, and substituted benzene derivatives. A substituent affects two aspects of the EAS reaction: 1.The rate of the reaction—A substituted benzene reacts faster or slower than benzene itself. 2.The orientation—The new group is located either ortho, meta, or para to the existing substituent.

37 Electrophilic Aromatic Substitution and Substituted Benzenes Consider toluene—Toluene reacts faster than benzene in all substitution reactions. The electron-donating CH 3 group activates the benzene ring to electrophilic attack. Ortho and para products predominate. The CH 3 group is called an ortho, para director.

38 Electrophilic Aromatic Substitution and Substituted Benzenes Consider nitrobenzene—It reacts more slowly than benzene in all substitution reactions. The electron-withdrawing NO 2 group deactivates the benzene ring to electrophilic attack. The meta product predominates. The NO 2 group is called a meta director.

39 Electrophilic Aromatic Substitution and Substituted Benzenes All substituents can be divided into three general types:

40 Electrophilic Aromatic Substitution and Substituted Benzenes

41 Electrophilic Aromatic Substitution and Substituted Benzenes Keep in mind that halogens are in a class by themselves. Also note that:

42 Electrophilic Aromatic Substitution and Substituted Benzenes To understand how substituents activate or deactivate the ring, we must consider the first step in electrophilic aromatic substitution. The first step involves addition of the electrophile (E + ) to form a resonance stabilized carbocation. The Hammond postulate makes it possible to predict the relative rate of the reaction by looking at the stability of the carbocation intermediate.

43 Electrophilic Aromatic Substitution and Substituted Benzenes The principles of inductive effects and resonance effects can now be used to predict carbocation stability.

44 Electrophilic Aromatic Substitution and Substituted Benzenes The energy diagrams below illustrate the effect of electron-withdrawing 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

45 Electrophilic Aromatic Substitution and Substituted Benzenes

46 Orientation Effects in Substituted Benzenes There are two general types of ortho, para directors and one general type of meta director. All ortho, para directors are R groups or have a nonbonded electron pair on the atom bonded to the benzene ring. All meta directors have a full or partial positive charge on the atom bonded to the benzene ring.

47 Orientation Effects in Substituted Benzenes To evaluate the effects of a given substituent, we can use the following stepwise procedure:

48 Orientation Effects in Substituted Benzenes A CH 3 group directs electrophilic attack ortho and para to itself because an electron-donating inductive effect stabilizes the carbocation intermediate.

49 Orientation Effects in Substituted Benzenes An NH 2 group directs electrophilic attack ortho and para to itself because the carbocation intermediate has additional resonance stabilization.

50 Orientation Effects in Substituted Benzenes With the NO 2 group (and all meta directors) meta attack occurs because attack at the ortho and para position gives a destabilized carbocation intermediate.

51 Orientation Effects in Substituted Benzenes Figure 18.7 The reactivity and directing effects of common substituted benezenes

52 Limitations in Electrophilic Aromatic Substitutions Benzene rings activated by strong EDGs—OH, NH 2, and their derivatives (OR, NHR, and NR 2 )—undergo polyhalogenation when treated with X 2 and FeX 3.

53 Limitations in Electrophilic Aromatic Substitutions A benzene ring deactivated by strong electron-withdrawing groups (i.e., any of the meta directors) is not electron rich enough to undergo Friedel-Crafts reactions. Friedel-Crafts reactions also do not occur with NH 2 groups because the complex that forms between the NH 2 group and the AlCl 3 catalyst deactivates the ring towards Friedel-Crafts reactions.

54 Limitations in Electrophilic Aromatic Substitutions Treatment of benzene with an alkyl halide and AlCl 3 places an electron- donor R group on the ring. Since R groups activate the ring, the alkylated product (C 6 H 5 R) is now more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation. Polysubstitution does not occur with Friedel-Crafts acylation.

55 1.When the directing effects of two groups reinforce, the new substituent is located on the position directed by both groups. Disubstituted Benzenes

56 2. If the directing effects of two groups oppose each other, the more powerful activator “wins out.” Disubstituted Benzenes

57 3. No substitution occurs between two meta substituents because of crowding. Disubstituted Benzenes

58 In a disubstituted benzene, the directing effects indicate which substituent must be added to the ring first. Synthesis of Benzene Derivatives Let us consider the consequences of bromination first followed by nitration, and nitration first, followed by bromination.

59 Pathway I, in which bromination precedes nitration, yields the desired product. Pathway II yields the undesired meta isomer. Synthesis of Benzene Derivatives

60 Benzylic C—H bonds are weaker than most other sp 3 hybridized C—H bonds, because homolysis forms a resonance-stabilized benzylic radical. Halogenation of Alkyl Benzenes As a result, alkyl benzenes undergo selective bromination at the weak benzylic C—H bond under radical conditions to form the benzylic halide.

61 Halogenation of Alkyl Benzenes

62 Note that alkyl benzenes undergo two different reactions depending on the reaction conditions: Halogenation of Alkyl Benzenes With Br 2 and FeBr 3 (ionic conditions), electrophilic aromatic substitution occurs, resulting in replacement of H by Br on the aromatic ring to form ortho and para isomers. With Br 2 and light or heat (radical conditions), substitution of H by Br occurs at the benzylic carbon of the alkyl group.

63 Arenes containing at least one benzylic C—H bond are oxidized with KMnO 4 to benzoic acid. Oxidation and Reduction of Substituted Benzenes Substrates with more than one alkyl group are oxidized to dicarboxylic acids. Compounds without a benzylic hydrogen are inert to oxidation.

64 Ketones formed as products of Friedel-Crafts acylation can be reduced to alkyl benzenes by two different methods: Oxidation and Reduction of Substituted Benzenes 1.The Clemmensen reduction—uses zinc and mercury in the presence of strong acid. 2.The Wolff-Kishner reduction—uses hydrazine (NH 2 NH 2 ) and strong base (KOH).

65 We now know two different ways to introduce an alkyl group on a benzene ring: Oxidation and Reduction of Substituted Benzenes 1.A one-step method using Friedel-Crafts alkylation. 2.A two-step method using Friedel-Crafts acylation to form a ketone, followed by reduction. Figure 18.8 Two methods to prepare an alkyl benzene

66 Although the two-step method seems more roundabout, it must be used to synthesize certain alkyl benzenes that cannot be prepared by the one-step Friedel-Crafts alkylation because of rearrangements. Oxidation and Reduction of Substituted Benzenes

67 A nitro group (NO 2 ) that has been introduced on a benzene ring by nitration with strong acid can readily be reduced to an amino group (NH 2 ) under a variety of conditions. Oxidation and Reduction of Substituted Benzenes

68 Summary of Chapter 15 Reaction Conditions

Reactions of H-X or X 2 with isolated and conjugated dienes. Conjugated dienes give 1,2 and 1,4- substituted products. Diels-Alder reaction between a conjugated diene and a dienophile. Retro-Diels-Alder reaction Diels-Alder reactions are promoted by EDGs on the diene and EWGs on the dienophile. 69 Summary of Chapter 16 Reaction Conditions

No new reactions: We covered benzene nomenclature and aromaticity. 70 Summary of Chapter 17 Reaction Conditions

71 Summary of Chapter 18 Reaction Conditions

72 Summary of Chapter 18 Reaction Conditions

Other Useful Reactions 73

Other Useful Reactions 74