Richard F. Daley and Sally J. Daley Organic. Chapter 18 Aromatic Substitution Reactions

Transcription

1 Richard F. Daley and Sally J. Daley rganic Chemistry Chapter 18 Aromatic Substitution Reactions 18.1 Mechanism of Aromatic Electrophilic Substitution The itration of Benzene alogenation and Sulfonation of Benzene Friedel-Crafts Alkylation and Acylation Effects of Monosubstituted Arenes on Substitution Rate Effects with Monosubstituted Arenes Classification of Substituents Friedel-Crafts Acylation 943 Synthesis of o-benzoylbenzoic Acid Multiple Substituent Effects Substitution on Polycyclic Arenes Diazotization 954 Synthesis of Methyl range 957 Sidebar - Sulfa Drugs ther Diazonium Salt Reactions ucleophilic Aromatic Substitution Benzyne 965 Synthesis of Trypticene Synthesis Examples 969 Key Ideas from Chapter

2 rganic Chemistry - Ch Daley & Daley Copyright by Richard F. Daley & Sally J. Daley All Rights Reserved. o part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the copyright holder.

3 rganic Chemistry - Ch Daley & Daley Chapter 18 Aromatic Substitution Reactions Chapter utline 18.1 Mechanism of Electrophilic Aromatic Substitution The mechanism of electrophilic substitution of benzene 18.2 The itration of Benzene A case study of aromatic electrophilic substitution 18.3 alogenation and Sulfonation of Benzene The mechanism of chlorination, bromination, and sulfonation of benzene 18.4 Friedel-Crafts Alkylation Formation of alkyl benzenes 18.5 Effects of Monosubstituted Arenes on Substitution The effects of one substituent on the position of reaction by a second substituent 18.6 Rate Effects with Monosubstituted Arenes The effect of one substituent on the rate of reaction by a second substituent 18.7 Classification of Substituents A listing of common substituents showing their directive and rate controlling effects 18.8 Friedel-Crafts Acylation Formation of acyl benzenes 18.9 Multiple Substituent Effects Predicting the position of substitution when two or more substituents are on the ring Substitution on Polycyclic Arenes Aromatic electrophilic substitution on polycyclic aromatic compounds Diazotization Diazotization and the use of the diazonium ion as an electrophile ther Diazonium Salt Reactions Replacement of the diazonium ion with a variety of groups ucleophilic Aromatic Substitution ucleophilic substitution on an aromatic ring Benzyne The formation and reaction of the reactive benzyne intermediate Synthesis Examples rganic synthesis using aromatic electrophilic substitution reactions

4 rganic Chemistry - Ch Daley & Daley bjectives Understand the mechanism for aromatic electrophilic substitution reactions Recognize appropriate electrophiles that will substitute on an aromatic ring Be able to predict the position of a new substitution on an aromatic ring with one or more existing substituents Know how the structure of one substituent affects the rate of reaction for adding a second substituent on the ring Know the diazotization reaction and how the diazonium salts react Understand the nucleophilic substitution reaction and its mechanism Be able to use the reactions in this chapter in synthesis Tis true; there s magic in the web of it... Shakespeare C hapter 17 presents the characteristics that make a compound aromatic. Understanding those characteristics is the foundation for this chapter, as it examines the various types of reactions that occur with aromatic hydrocarbons. The chapter first discusses electrophilic aromatic substitution a major aromatic hydrocarbon mechanistic type. Electrophilic substitution allows you to directly introduce a variety of functional groups onto the aromatic ring. The chapter then looks at several examples of electrophilic substitutions on benzene and its derivatives. Much of the rest of the chapter discusses how the substituents already on the ring affect the placement of additional substituents Mechanism of Electrophilic Aromatic Substitution Chapter 14 discusses electrophilic addition reactions to the π bond of an alkene. The result of an electrophilic addition reaction is

5 rganic Chemistry - Ch Daley & Daley that a new atom or group of atoms adds to both carbons involved in the double bond. The mechanism proceeds in two steps: The electron cloud of the π bond reacts with the electrophile to form an intermediate carbocation. A nucleophile adds to the intermediate carbocation, thus replacing the π bond with two new σ bonds. E E u: u E The Ad E 2 mechanism. Benzenoid aromatic compounds contain benzene rings or fused benzene rings. Benzenoid aromatic compounds also have an electron-rich π bond cloud that is susceptible to attack by an electrophile. As with an alkene, the π electron cloud of the benzenoid aromatic compound reacts with the electrophile and adds the electrophile to one of the carbons in the ring. This reaction produces a carbocation intermediate. Step 1 The complex formed by the attack of the electrophile A σ complex is a resonance-stabilized carbocation intermediate. The carbocation intermediate, called a σ complex, is not aromatic. The σ complex is written as follows to show the delocalization of the positive charge: + E

6 rganic Chemistry - Ch Daley & Daley The carbon receiving the electrophile becomes sp 3 hybridized. aving an sp 3 hybrid carbon in the ring interrupts the continuous overlap of the p orbitals, which prevents continuous electron delocalization all the way around the ring and causes the benzene ring to lose its aromaticity. At this point, the electrophilic addition reaction with benzene ends its similarity to an electrophilic addition with an alkene. As you may recall from Chapter 17, compounds that can become aromatic will. So it is with the σ complex. The closed shell of benzene is so stable that the σ complex rapidly loses a proton to a base, enabling the reaction to regenerate the aromatic benzene ring. If the nucleophile attacked the aromatic ring the reaction would have formed a substituted cyclohexadiene, and the benzene ring would have permanently lost its aromaticity. owever, because the aromatic ring is more stable than the cyclohexadiene ring, an attack of a nucleophile on the ring would require an endothermic process rather than an exothermic process. Thus, the lower energy pathway is the loss of a proton to regenerate the now substituted benzene ring. Step 2 Base: Electrophilic aromatic substitution is a reaction in which an electrophile displaces another atom. Because an electrophile substitutes itself for a hydrogen on the ring, the reaction s overall type is an electrophilic substitution instead of an electrophilic addition. This reaction type is called an electrophilic aromatic substitution. Exercise 18.1 The previous illustration of the second step of an electrophilic aromatic substitution shows the reaction of only one of the three resonance structures of the σ complex formed in step one. Show the second step from each of the other two resonance structures of the σ complex. In an electrophilic aromatic substitution reaction, the σ complex is an intermediate, not a transition state. The reaction is not concerted; the bond to the electrophile forms before the bond to the proton breaks. Chemists have gathered much experimental evidence to verify this process. Thus, when drawing a reaction progress

7 rganic Chemistry - Ch Daley & Daley diagram, such as Figure 18.1, place the σ complex ion in a valley between the two transition states. + E + E G 2 + E G 1 + E G o + Reaction Progress Figure Reaction progress diagram for electrophilic aromatic substitution. The reaction progress diagram in Figure 18.1 shows that the first step in the mechanism of an electrophilic substitution reaction is the rate-determining step. ote that G 1, the free energy of activation for the reaction of benzene and the electrophile to form the σ complex, is greater than G 2, the free energy of activation for the reaction of the σ complex with the nucleophile to form the final product. Because the resonance energy in the benzene ring is lost when forming the σ complex, the reaction of the electrophile with benzene to form the σ complex is endothermic, and it proceeds slowly. As the σ complex loses the proton and the benzene ring regains its resonance energy, the reaction is exothermic and proceeds rapidly. Electrophilic aromatic substitution is the most common method used to synthesize substituted aromatic compounds. The reaction directly introduces functional groups onto the benzene ring and works with a variety of electrophilic reagents. Sections 18.2, 18.3, and 18.4 discuss the major electrophilic aromatic substitution reactions. All these reactions follow the mechanism presented in this section The itration of Benzene Benzene reacts slowly with hot concentrated nitric acid in an electrophilic aromatic substitution reaction to form nitrobenzene. This reaction is potentially dangerous, however, because nitric acid is a strong oxidizing agent that often explodes in the presence of any material that readily oxidizes. A safer, faster, and more convenient synthesis employs a mixture of concentrated nitric acid and

8 rganic Chemistry - Ch Daley & Daley The nitration of benzene is the reaction of a benzenoid compound with the 2 electrophile. concentrated sulfuric acid. The concentrated sulfuric acid acts as a catalyst allowing nitration to take place more readily at more moderate temperatures. 3 2 S oC itrobenzene (85%) Dehydration of alcohols is discussed in Section 13.9, page 000. The nitronium ion ( ) is the electrophile in the nitration of benzene to form nitrobenzene. Although concentrated nitric acid produces the nitronium ion by itself, the equilibrium is so far to the left that the process is slow. Adding concentrated sulfuric acid to the reaction mixture increases the concentration of the nitronium ion, thereby increasing the rate of the nitration reaction. The nitronium ion forms via a pathway similar to the first step in the dehydration of an alcohol. S 3 After the nitronium ion forms, it reacts with benzene to form the σ complex, the first step of the electrophilic aromatic substitution reaction. This step is slow because the σ complex is not aromatic. Additionally, the σ complex is higher in energy than the benzene and the nitronium ion. + σ complex In the next step of the mechanism, the σ complex loses a proton to form nitrobenzene. This step is rapid because the loss of a proton allows the molecule to become aromatic again.

9 rganic Chemistry - Ch Daley & Daley As you may recall, wavenumbers are inversely proportional to wavelength. Thus, higher energy = lower wavenumbers. See Section 9.2, page 000 for more details. Chemists tested whether the loss of a proton is the fast step or the slow step of an electrophilic aromatic substitution by replacing the hydrogens in benzene with deuterium and then running the reaction. Deuterium ( 2 abbreviated as D) is an isotope of hydrogen ( 1 ) that contains not only one proton in its nucleus but also one neutron. Thus, deuterium has twice the mass of hydrogen. Because the bond energy between a pair of atoms changes in proportion to the masses of the isotopes involved in that bond, the C D bond is higher in energy than the C bond. This isotope effect is observable in the IR spectrum. The IR absorption of the C bond in benzene is approximately 3050 cm 1; whereas the C D bond of deuteriobenzene is about 2150 cm 1. Because breaking a C D bond requires more energy than breaking a C bond, a reaction whose rate-determining step involves breaking a C bond proceeds more slowly when deuterium is present. Thus, replacing C 6 6 with C 6 D 6 results in a reduction of the nitration rate if the breaking of a C bond is the ratedetermining step. With the electrophilic aromatic substitution reaction, chemists measured no difference in the rate of reaction between C 6 D 6 and C 6 6. This shows that the rate-determining step is the formation of the σ complex, not the step that breaks the C bond. Solved Exercise 18.1 Show a mechanism for the following reaction. D 2 S 4 D Solution In this reaction, a deuterium replaces one of the hydrogens on the ring. The D 2 S 4 is the source of D electrophile. The formation of the σ complex involves reaction of the ring with the electrophile. D S 3 D D

10 rganic Chemistry - Ch Daley & Daley The DS 4 - anion removes the proton to form the final product. D S 3 D D Exercise 18.2 Write a mechanism for the formation of a nitronium ion from nitric acid alone alogenation and Sulfonation of Benzene The conversion of benzene to bromobenzene or chlorobenzene by electrophilic aromatic substitution requires the presence of a Lewis acid in a mixture of benzene and the halogen (usually Cl 2 or 2 ). The most common laboratory procedure involves adding the halogen to benzene in the presence of some metallic iron. Chemists frequently add this iron by tossing a few carpet tacks into the reaction mixture. To provide the iron in an industrial setting, the reaction is run in iron reaction vessels. The iron itself is not actually the reaction catalyst. The iron reacts with the halogen to form a small amount of iron(iii) chloride or iron(iii) bromide. These iron halides are the catalysts: 2Fe + 3Cl 2 2FeCl 3 2Fe Fe 3 By themselves, bromine and chlorine are weakly electrophilic. owever, neither halogen is electrophilic enough to react with benzene. The iron halides are Lewis acids and form complexes with the halogen atoms. Cl Cl FeCl 3 Cl Cl FeCl 3 Fe 3 Fe 3 The formation of the bromine iron(iii) bromide complex increases the electrophilicity of the bromine to the point that it can attack the benzene ring and form a σ complex. The next step, in which

11 rganic Chemistry - Ch Daley & Daley the - Fe 4 ion removes the proton from the σ complex producing bromobenzene,, and Fe 3, is quick. Fe 3 Fe 3 Figure 18.2 shows the reaction progress diagram for the bromination of benzene. ote that G 2 < G 1, so formation of the σ complex is the rate-determining step. + + G 2 + G G o + Reaction Progress Figure The reaction progress diagram for the bromination of benzene. Chlorination of benzene follows a similar route to the bromination of benzene. The catalyst, FeCl 3, forms from the reaction of iron and chlorine. n some occasions, chemists also use AlCl 3 as a catalyst. Section 18.4 discusses the uses of AlCl 3 as a strong Lewis acid and its importance in other electrophilic substitutions. Cl 2 FeCl 3 Cl Chlorobenzene (83%)

12 rganic Chemistry - Ch Daley & Daley Section 18.12, page 000, describes an indirect method of monofluorinating a benzene by using an intermediate diazonium compound. Iodine may also be introduced via the diazonium compound (Section 18.12, page 000). Fluorination of benzene is a very exothermic reaction. It reacts so rapidly that it requires special conditions and reaction vessels. Even then, the reaction rarely stops with a monofluorination product. Iodine is so unreactive that it requires special techniques to iodinate directly. These techniques involve adding iodine to the reaction mixture in the presence of a strong oxidizing reagent such as nitric acid. I 2 3 I Iodobenzene (86%) Exercise 18.3 An important technique for the introduction of fluorine onto an aromatic ring is via a two-step thallation procedure. Benzene reacts with thallium trifluoracetate (Tl(CCF 3 ) 3 ) to form an organothallium intermediate. This intermediate reacts with KF and BF 3 to form the fluorobenzene. Tl(CCF 3 ) 3 Tl(CCF 3 ) 2 KF, BF 3 F Propose a mechanism for the first step of this reaction. In a sulfonation reaction, benzene reacts with sulfuric acid to produce benzenesulfonic acid. 2 S 4 S 3 Benzenesulfonic acid (95%)

13 rganic Chemistry - Ch Daley & Daley Azeotropic distillation is discussed in Section 8.2, page 000. Benzene and water form an azeotrope boiling at 69.4 o C having a composition of 91% benzene and 9% water. A sulfonation reaction is readily reversible and yields only low amounts of benzenesulfonic acid because the equilibrium constant favors the substrate. owever, good yields of benzenesulfonic acids are obtained by removing the water from the reaction mixture. For example, an azeotropic distillation removes the water along with the unreacted benzene, leaving the benzenesulfonic acid. Another way to remove the water and increase the yield of benzenesulfonic acid is to use fuming sulfuric acid as the source of the electrophile. The actual electrophile, or sulfonating agent, is sulfur trioxide regardless of whether you use sulfuric acid or fuming sulfuric acid. When you use fuming sulfuric acid, you increase the amount of sulfur trioxide available to act as the electrophile. Because the sulfur trioxide reacts with the water to form sulfuric acid, the sulfur trioxide also removes the water as soon as it forms. Chemists form fuming sulfuric acid by adding sulfur trioxide to concentrated sulfuric acid. S S 4 An advantage of the sulfonation reaction is its reversibility. Simply heating benzenesulfonic acid with an aqueous acid removes the sulfonic acid group. Reversibility is a very useful synthetic tool as you can synthesize a benzenesulfonic acid, use it as a synthetic intermediate, and then remove the sulfonic acid group when it is no longer needed. The mechanism for the formation of benzenesulfonic acid follows the same general mechanism as do all electrophilic aromatic substitution reactions. The first step is the attack of benzene on the sulfur of sulfur trioxide, followed by the loss of a proton, which allows the ring to regain its aromaticity. S S S 3 S 3 Exercise 18.4 Write a mechanism to explain the presence of S 3 in sulfuric acid.

14 rganic Chemistry - Ch Daley & Daley 18.4 Friedel-Crafts Alkylation The Friedel-Crafts reaction uses a carbocation or acylium ion as the electrophile with benzenoid aromatic compounds. In 1877, Charles Friedel at the Sorbonne in Paris and James M. Crafts of the Massachusetts Institute of Technology collaborated on the development of a method to produce alkylbenzenes and acylbenzenes. Their method, the Friedel-Crafts reaction, is one of the most useful synthetic methods in organic chemistry because it allows the introduction of a carbon side chain to benzene. The formation of an alkyl benzene in a Friedel-Crafts alkylation involves benzene, an alkyl halide, and a Lewis acid. Frequently, the Lewis acid used is aluminum chloride. C 3 C 2 Cl C 2 C 3 AlCl 3 Ethylbenzene (84%) Carbocation rearrangements are introduced in Section 12.4, page 000. The mechanism for an alkylation reaction begins as the Lewis acid, in this case AlCl 3, reacts with the alkyl halide to form a complex. This complex is the reacting species for a primary alkyl halide. For a tertiary alkyl halide, the complex tends to dissociate forming a free carbocation. In addition, if a carbocation-like rearrangement of the alkyl group can occur, it will. C 3 C 2 AlCl 3 C 3 C 2 Cl AlCl 3 Cl The benzene ring then undergoes electrophilic attack by the complex to form a σ complex completing the first step of the electrophilic aromatic substitution reaction. Immediately following the first step, the σ complex undergoes the second step and loses a proton to form the alkyl benzene.

15 rganic Chemistry - Ch Daley & Daley C 3 C 2 Cl AlCl 3 C 2 C 3 AlCl 4 C 2 C 3 Rearrangement of the alkyl group can occur during a Friedel- Crafts alkylation, so the product of the alkylation is almost never exclusively a primary alkyl benzene, unless the primary carbocation cannot rearrange. For example, the reaction of 1-chloropropane with benzene in the presence of aluminum chloride produces isopropylbenzene and propyl benzene in a 2:1 ratio. C(C 3 ) 2 67% C 3 C 2 C 2 Cl AlCl 3 Isopropylbenzene C 2 C 2 C 3 33% Propylbenzene The electrophile for the isopropylbenzene product is an isopropyl complex that formed when the alkyl halide lost the chlorine ion and a hydride shift occurred. C 3 C 2 C 2 Cl AlCl 3 C 3 CC 2 Cl AlCl 3 C 3 CC 3 Cl AlCl 3

16 rganic Chemistry - Ch Daley & Daley As you may recall from Section 12.5 (page 000), more highly substituted carbocations are more stable. The driving force for the rearrangement is the stability of the carbocations (3 o > 2 o > 1 o ). The rearrangement of the carbocation is a major limitation of the synthetic utility of the Friedel-Crafts reaction. The reaction generally works well if the desired product comes from the more stable carbocation. Solved Exercise 18.2 What product forms in the following reaction? C 2 Cl AlCl 3 Solution In the presence of a Lewis acid catalyst like AlCl 3, benzyl chloride forms the benzyl cation. The benzyl cation is the electrophile that reacts with the benzene to form diphenylmethane. C 2 Cl C 2 AlCl 3 Diphenylmethane Exercise 18.5 Propose a step-by-step mechanism for the synthesis of cyclopentylbenzene from benzene, chlorocyclopentane, and aluminum chloride. Lewis acids other than AlCl 3 catalyze Friedel-Crafts reactions. These catalysts include most any Lewis acid that can form a carbocation from an alkyl halide. Some examples are FeCl 3, ZnCl 2, and BF 3. Chapters 12 through 14 cover a number of reactions involving carbocations. Electrophilic attack on benzene by a carbocation is simply another of those reactions. Any reagent that forms a carbocation, not just the ones specifically mentioned in this chapter, can catalyze a Friedel-Crafts alkylation. For example, a mixture of propene and liquid hydrogen fluoride, being used as both solvent and proton donor, reacts with benzene to produce isopropylbenzene.

17 rganic Chemistry - Ch Daley & Daley C 3 C C 2 F C(C 3 ) 2 Isopropylbenzene (75%) Exercise 18.6 Write a step-by-step mechanism for the reaction of cyclopentene with benzene in liquid F. Alcohols in acidic media undergo reactions that are comparable to the reactions of alkyl halides with Lewis acids. Just like the alkyl halides, alcohol substrates also readily rearrange as they lose the group to form the carbocation. For example, isobutyl alcohol with boron trifluoride (BF 3 ) as a catalyst, reacts with benzene to produce tert-butylbenzene. The reaction produces tert-butylbenzene instead of isobutylbenzene because a hydride shift in the isobutyl alcohol occurs at the same time that it loses the group, thus producing the more stable carbocation intermediate. (C 3 ) 2 CC 2 C(C 3 ) 3 BF 3 tert-butylbenzene (64%) 18.5 Effects of Monosubstituted Arenes on Substitution So far, you have investigated only those reactions that involve various electrophilic reagents with benzene. This section begins the discussion of electrophilic aromatic substitution reactions that occur with benzene rings already bearing a substituent. An electrophilic substitution with a monosubstituted benzene greatly affects the outcome of the reaction compared to an electrophilic substitution on a nonsubstituted benzene. The substituent already on the benzene ring affects the reaction in two important ways: it affects the regiochemistry of the incoming electrophile and the rate of the reaction. For example, the nitration of toluene produces three products in differing amounts. nly 3% of the product forms with the nitro group in the position meta to the methyl group, whereas the

18 rganic Chemistry - Ch Daley & Daley remaining 97% forms in the ortho and para positions (63% ortho and 34% para. C 3 C 3 C 3 C S 4 o-itrotoluene 63% m-itrotoluene 3% p-itrotoluene 34% An ortho, para directing group guides an incoming electrophile to either the ortho or para position on the ring. Because toluene produces predominantly ortho and para substitution products, the methyl substituent is called an ortho, para directing group. Exercise 18.7 Statistically what percentage of each nitrotoluene product would you expect to get? In the nitration of (trifluoromethyl)benzene, on the other hand, 91% of the product forms with the nitro group in the position meta to the trifluoromethyl group. The other 9% of the product is divided with 6% in the ortho position and 3% in the para position. CF 3 CF 3 2 CF 3 CF S (Trifluoromethyl) benzene o-itro(trifluoromethyl)benzene m-itro(trifluoromethyl)benzene 6% 91% 3% p-itro(trifluoromethyl)benzene A meta directing group guides an incoming electrophile to the meta position on the ring. Because substitution in (trifluoromethyl)benzene occurs primarily at the meta position, the trifluoromethyl group is called a meta director. The nitration of toluene and (trifluoromethyl)benzene illustrates how the substituent already present on the benzene ring affects the regioselectivity of an electrophile in a substitution reaction.

19 rganic Chemistry - Ch Daley & Daley The existing substituent gains its influence over the location of an incoming group by either donating electron density to or withdrawing electron density from the π electron cloud. Electron donating substituents (e.g. C 3 ) direct incoming electrophiles primarily to the ortho and para positions. Electron-withdrawing substituents (e.g. CF 3 ) direct incoming electrophiles to the meta position. The directing effect of the existing substituent group on the arene is based on the interaction of that group with the positive charge of the σ complex. When the substituent group stabilizes the σ complex by its electron-donating qualities, it directs the incoming group primarily to the ortho and para positions. When the substituent group destabilizes the σ complex by withdrawing electron density from the benzene ring, the electrophile reacts mostly to the meta position. The following discussion of toluene gives a practical explanation as to why the ortho- and para-substituted σ complexes are more stable than the meta-substituted σ complex. rtho Substitution C 3 2 C 3 2 C 3 C 3 Para Substitution C 3 C 3 As you look at the three resonance contributors of the σ complex for the ortho and para substitutions, notice that both complexes contain one 3 o carbocation (the one with positive charge on the carbon bearing the methyl group) and two 2 o carbocations. The tertiary carbocation is much more stable than either of the two secondary carbocations, so the tertiary carbocation adds overall stability to the ortho- and parasubstituted σ complexes.

20 rganic Chemistry - Ch Daley & Daley C 3 Site of the more stable tertiary carbocation. C 3 rtho complex Para complex n the other hand, the three resonance structures with the meta-substituted σ complex are all secondary carbocations. Meta Substitution C 3 C 3 C 3 The donating character of alkyl groups is introduced in Section 7.5, page 000. The meta-substituted σ complex is much less stable than the orthoand para-substituted σ complexes. A methyl group is an electron-donating group, and although it activates all three positions relative to benzene, it activates the ortho and para positions more than the meta positions. This increased reactivity at the ortho and para sites directs the incoming electrophiles primarily to those positions. All alkyl groups are electron donating; thus, they are all ortho, para directing groups. In contrast to the methyl group, the trifluoromethyl group is strongly electron withdrawing. Because of the high electronegativity of the fluorines, the C F bond is quite polar with the positive end of the dipole at the carbon. F F F C When a resonance contributor from a trifluoromethyl σ complex has the positive charge on the carbon bearing the trifluoromethyl group, the positive charge from the trifluoromethyl dipole and the positive charge from the resonance contributor repel each other. This repelling behavior destabilizes that carbocation, and thus destabilizes the whole

21 CF 3 CF 3 CF 3 rganic Chemistry - Ch Daley & Daley σ complex. Both the ortho and the para σ complexes have one resonance contributor with a positive charge on the carbon bearing the CF 3 group; whereas, none of the resonance contributors in the meta σ complex has a positive charge on the carbon bearing the CF 3 group. rtho Substitution CF 3 Para Substitution CF 3 CF 3 CF 3 Meta Substitution CF 3 CF 3 The positive charge on the carbon of the ring and the partial positive charge on the trifluoromethyl group strongly destabilize the ortho and para σ complexes. + CF 3 These positive sites repel one another. + CF 3 rtho complex Para complex An electrophilic attack at the meta position leads to a more stable intermediate σ complex than does an electrophilic attack at

22 rganic Chemistry - Ch Daley & Daley either the ortho or para positions. Although the trifluoromethyl group deactivates all three positions in comparison to benzene, it deactivates the meta position less when compared to either the ortho or para positions Rate Effects with Monosubstituted Arenes Formation of the σ complex is the rate-determining step in electrophilic substitution reactions. Factors that affect the stability of the σ complex also affect the rate at which it forms. Thus, substituents on a benzene ring not only affect the position of an incoming electrophile takes on that ring, but also affect the rate of reaction. Some substituents speed up the rate of reaction in comparison to benzene s rate, and some slow it down. As with regioselectivity, the more stable the σ complex, the easier the σ complex forms, and the faster it forms. The data in Table 18.1 shows the relative rates for the nitration of benzene, toluene, and (trifluoromethyl)benzene. ote that the rate of reaction for the ortho and para positions of toluene is about one million times faster than for the ortho and para positions of (trifluoromethyl)benzene. ote also that the meta position of toluene is over 30,000 times as reactive as the meta position of (trifluoromethyl)benzene. bserve that the rates for reaction at the ortho position are lower than for the para position. owever, experimentally there is twice as much ortho product as para product. This is due to the fact that there are two ortho hydrogens and only one para hydrogen. Relative Rates Benzene Toluene (Trifluoromethyl)benzene rtho x 10 6 Meta x 10 6 Para x 10 6 Table Relative rates for the nitration of benzene, toluene, and (trifluoromethyl)benzene. An activating ortho, para directing group reacts faster than benzene and directs an incoming electrophile to the ortho and para positions. Recall from Section 18.5 that, when one resonance contributor in a σ complex possesses more stability than the rest of the resonance contributors, the more stable contributor increases the overall stability of the entire σ complex. In fact, it increases the stability of the whole chemical species. Looking again at the example of toluene, both the ortho σ complex and the para σ complex have one resonance contributor that is more stable than the other contributors. one of

23 rganic Chemistry - Ch Daley & Daley the meta σ complex contributors are more stable than the others. evertheless the meta σ complex benefits from the electron-donating ability of the methyl group. Thus, the σ complex from toluene is more stable than the σ complex formed from benzene, and it reacts faster than benzene in electrophilic aromatic substitution reactions. The presence of the methyl group increases the rate of reaction of toluene at all three sites, especially the ortho and para positions. Because of this increased rate of reaction in comparison to benzene, the methyl group is called an activating ortho, para director. The greater the stability of the product of a reaction in a family of related reactions, in this case the intermediate σ complex, the less energy of activation required to form it. Figure 18.3 shows the relationship of the energies of activation for the formation of benzene s one σ complex and toluene s three. All three σ complexes from the reaction of toluene are more stable than the σ complex from benzene; therefore, they need less energy to form. Figure 18.3 also shows the energy relationship among the various σ complexes of toluene. Recall from Section 18.5 that 63% of the product forms in the ortho position and 34% in the para position. Thus, the ortho position has nearly twice as much substitution as does the para position. Because there are two ortho sites and only one para site, you would expect exactly a 2:1 ratio of product if both had identical reactivity. owever, the methyl group sterically hinders the ortho position slightly, which causes the reaction to require more energy to place the electrophile in an ortho position. + G 1 Meta rtho Para + C 3 + Reaction Progress Figure The relative activation energies for the formation of the σ complexes of benzene and ortho, meta, and para substitutions in toluene.

24 rganic Chemistry - Ch Daley & Daley A deactivating meta directing group reacts slower than benzene and directs an incoming electrophile to the meta position. As you saw in Section 18.5, the trifluoromethyl group is electron-withdrawing in electrophilic aromatic substitution reactions and destabilizes the σ complexes in comparison to the σ complex of benzene. The trifluoromethyl group destabilizes the ortho σ complex and para σ complex the most because both have a resonance contributor with the positive charge on the carbon bearing the CF 3 group. Although the meta σ complex is the most stable, it is less stable than benzene. The CF 3 electron-withdrawing group destabilizes the meta σ complex because the electron-withdrawing group is only one carbon away from the destabilized ortho and para resonance contributors. All three σ complexes are less stable than benzene and therefore take longer to react. Thus, the CF 3 group is called a deactivating meta director. Figure 18.4 shows the relationship of the activation energies and the σ complexes of benzene and the ortho, meta, and para positions of (trifluoromethyl)benzene. G 1 + rtho Para Meta CF Reaction Progress Figure The relative activation energies for the formation of the σ complexes of benzene and ortho, meta, and para substitutions in (trifluoromethyl)benzene. Exercise 18.8 The rate of nitration of 1,3-dimethylbenzene (m-xylene) is 100 times as fast as 1,4-dimethylbenzene (p-xylene). Predict the product(s) of nitration for both xylenes. If there are more than one isomer, which would you expect to be the major product? Explain the difference in the relative rates Classification of Substituents

25 rganic Chemistry - Ch Daley & Daley Methyl and trifluoromethyl groups are only two of the many substituents that affect the way electrophiles react with benzene in substitution reactions. In regard to regioselectivity, all substituent groups are either ortho, para directors or meta directors. Each group varies as to how it affects the rate of electrophilic substitution. In general, ortho, para directors activate the aromatic ring with respect to benzene, and meta directors deactivate the ring. The ortho, para directors all share the ability to stabilize the σ complex. For example, the following four resonance contributors can be written for para substitution on anisole. C 3 C 3 C 3 C 3 E E E E The first three resonance structures are identical to the ones drawn for para-substituted toluene in Section The fourth resonance structure, however, is particularly stable because the nonbonding pair of electrons on the oxygen atom helps stabilize the positive charge. In fact, this is the major resonance contributor because all the atoms have filled orbitals in their valence shells. All meta directors inductively destabilize the σ complex because they have a partial positive or a full positive charge on the atom attached to the ring thereby discouraging substitution at sites ortho or para to the substituent. By default, the reactive site is the meta position because it is not directly destabilized by the substituent. For example, the least stable resonance contributor for nitrobenzene has a positive charge on the carbon bearing the nitrogen. The nitro group nitrogen also has a formal positive charge. E

26 rganic Chemistry - Ch Daley & Daley Table 18.2 summarizes the rate and orientation effects of the most common substituents. The list places the substituents in order of decreasing rate of substitution. Amines are the most activating group, and nitro groups are the strongest deactivating group. Effect on Rate Substituent Product rientation Very strongly activating 2 rtho, Para R R 2 rtho, Para rtho, Para Strongly activating CR rtho, Para rtho, Para R rtho, Para Activating Reference Deactivating Strongly deactivating CR R Ar C=CR 2 X (X=F,Cl,,I) C 2 X CR rtho, Para rtho, Para rtho, Para rtho, Para rtho, Para rtho, Para Meta

27 rganic Chemistry - Ch Daley & Daley Effect on Rate Substituent Product rientation C CR Meta Meta Meta C Very strongly deactivating CCl Meta C Meta S 3 CF 3 3 R 3 Meta Meta Meta Meta Meta Table Classification of substituents in electrophilic aromatic substitution reactions. The following five rules summarize Table 18.2: 1) Activating substituents are ortho, para directors. 2) rtho, para directors, except for alkyl, aryl, and vinyl groups, have nonbonding electrons on the atom attached to the aromatic ring. 3) Deactivating substituents are meta directors. 4) Meta directing groups have at least a partial positive charge on the atom that bonds to the ring carbons. 5) alogens are an exception to the above rules. They are deactivating, but are ortho, para directing groups, and they have nonbonding electrons.

28 rganic Chemistry - Ch Daley & Daley Phenol is an example of an ortho, para director with nonbonding electrons. In a nitration substitution reaction of phenol, both the ortho σ complex and the para σ complex have four resonance contributors. The first three are identical to the three shown in Section 18.5 for either toluene or (trifluoromethyl)benzene. In the fourth one, the oxygen contributes a pair of nonbonding electrons to the electron deficient carbon to form a carbon oxygen double bond. All the atoms in this resonance contributor have an octet of electrons, so this contributor is more stable than the other three. rtho Substitution Major contributor Para Substitution Major contributor The stabilization of the positive charge of the σ complex by the oxygen makes it the major resonance contributor. This stability provided by the major contributor permits the σ complex to form rapidly. The rate of formation of the σ complex from phenol in an electrophilic substitution is much faster than the reaction of the σ complex of benzene. In fact, the nitration of phenol is approximately 50,000 times faster than the nitration of benzene. The nonbonding pairs of electrons on the oxygen cannot stabilize the meta σ complex of phenol because none of the resonance contributors have a positive charge on the carbon bearing the group. Thus, the meta σ complex has only three resonance contributors. The rate of reaction for the meta position, although slower than the ortho or para positions, is still 10.4 times faster than the rate of reaction with benzene. Meta Substitution

29 rganic Chemistry - Ch Daley & Daley Beyond what Section 18.6 presents about substitution reactions on a ring containing an electron-withdrawing substituent, you need to know that the greater the partial positive charge on the substituent, the more deactivating the group. The halogens are an exception to the general rules of how substituents on benzene behave. The halogen substituents are electronegative; thus, they are electron withdrawing. They induce a partial positive charge on the carbon bearing the halogen and thereby deactivate the ring. owever, unlike other deactivating groups, halogens direct the electrophile to the ortho and para positions because they have nonbonding pairs of electrons available to stabilize the σ complex. The stabilization is less significant than with a phenol or aniline, even though oxygen and nitrogen have electronegativities equal to or greater than the halogens. The lower stabilization by the halogens is because the nonbonding electrons are further from the ring and thus less likely to be donated to stabilize the σ complex. In the nitration of bromobenzene for example, the bromine deactivates the ring causing the reaction to be 20 times slower than the nitration of benzene. The primary products are o- bromonitrobenzene and p-bromonitrobenzene. 3 2 S % 1% 60% The halogens direct the incoming electrophile to the ortho and para positions because their nonbonding electrons stabilize the ortho and para σ complexes but not the meta σ complex. The major resonance contributor for the halogen-bearing σ complex has the positive charge on the halogen atom. All atoms in this structure have an octet of electrons; thus, it is the most stable resonance contributor.

30 rganic Chemistry - Ch Daley & Daley Both resonance contributors have full octets on all atoms. Exercise 18.9 Aniline (C ) is more reactive towards electrophilic substitution than is acetanilide (C 6 5 CC 3 ). Explain this difference in reactivity. When using highly activating substituent groups, limiting the number of incoming substituents to only one is difficult. For example, phenol reacts rapidly with bromine in water to form a quantitative yield of 2,4,6-tribromophenol ,4,6-Tribromophenol (100%) Solved Exercise 18.3 Complete the following reactions showing the major monosubstitution product(s) from each reaction. a) 2 Fe Solution

31 rganic Chemistry - Ch Daley & Daley omine is a weakly deactivating ortho, para directing group. Thus, you will get a mixture of ortho and para substitution products. Because bromine is large, there will be a larger fraction of para than ortho product. 2 Fe + b) C 3 C3 C 2 C 2 Cl AlCl 3 Solution The methoxy group is an activating ortho, para directing group. Thus, you will get a mixture of ortho and para substitution. Because the oxygen is small, the ortho product will likely predominate. In this case, the electrophile will rearrange to form a secondary carbocation. Thus, the product is an isopropyl-substituted anisole. C 3 C 3 C 3 C 2 C 2 Cl + C 3 AlCl 3 CC 3 C 3 C 3 C C 3 c) CC S 4 Solution The ester functional group is a deactivating meta directing group. Thus, the product will have a nitro group substituted meta to the ester group.

32 rganic Chemistry - Ch Daley & Daley CC S 4 CC Friedel-Crafts Acylation Section 18.4 describes the Friedel-Crafts alkylation reaction. As you may recall, the reaction has a limitation in that, if possible, an alkyl group will rearrange to form the more stable carbocation. A second limitation of the Friedel-Crafts alkylation is that it does not reliably produce a monoalkyl benzene. The reaction produces a slightly activated aromatic ring, which then undergoes a second alkylation at a higher rate than does benzene. C 3 C 3 C 3 C 3 Cl AlCl 3 C 3 Cl AlCl 3 + C3 The product is more reactive than the substrate, so it readily undergoes further reaction. C 3 A third limitation of the Friedel-Crafts reaction is that it does not proceed well with deactivated benzene rings. Any group more deactivating than the halogens normally gives a low yield or no reaction at all in the Friedel-Crafts reaction. A variation of the Friedel-Crafts reaction is the acylation reaction. A Friedel-Crafts acylation reaction involves the reaction of an acyl halide or an acid anhydride and a Lewis acid with benzene to yield an acylbenzene. Both the acyl halide and the anhydride work well in this reaction because each possesses a good leaving group. The acyl halide has a halide ion leaving group and the acid anhydride has a carboxylate ion leaving group. The Friedel-Crafts acylation produces a deactivated ring and, because deactivated rings cannot undergo a second acylation, the reaction stops at that point.

33 rganic Chemistry - Ch Daley & Daley C 3 CCl CC 3 AlCl 3 The product is less reactive than the substrate, so it does not undergo further reaction. Unlike an alkylation reaction, which needs only catalytic amounts of AlCl 3 to react, an acylation reaction requires one mole of AlCl 3 per mole of acyl halide. Acylation reactions need this stoichiometric amount of aluminum chloride because the aluminum chloride first forms an acid/base complex with the carbonyl group of the acyl halide. When running an acylation reaction, chemists usually allow the acid/base complex to form before they add the benzene to the reaction mixture. C 3 C 2 CCl AlCl 3 C 3 C 2 CCl AlCl 3 Acid-base complex The acid/base complex is relatively stable in low polarity solvents. In higher polarity solvents, however, it ionizes and forms a resonancestabilized acyl (or acylium) cation. AlCl 3 C 3 C 2 C C 3 C 2 CCl C 3 C 2 C Acyl cation An acyl cation reacts with benzene in much the same way as any other electrophile.

34 rganic Chemistry - Ch Daley & Daley C 3 C 2 C CC 2 C 3 AlCl 4 CC 2 C 3 Chemists use anhydrides to generate the acylium ion less frequently than they use acyl halides because only a few anhydrides are commonly available. In addition, acid anhydrides are expensive and only half the material is available for reaction. The other half is thrown away. The following mechanism shows the use of an anhydride in a Friedel-Crafts acylation reaction. RC CR AlCl 3 RC + Cl 3 Al CR Exercise In some low polarity solvents, the acid/base complex does not readily form the acylium ion. Thus, the acid/base complex is the reacting species. Write a mechanism for this reaction. (int: Refer to Chapter 8 for a starter.) The acylationreduction sequence involves the synthesis of a 1-phenyl ketone followed by the conversion of the carbonyl to a C 2 group. In contrast to Friedel-Crafts alkylation reactions, the cations in Friedel-Crafts acylation reactions do not rearrange. Thus, the acyl group in the acyl benzene product has the same structure as the acyl group in the acyl halide substrate. Rearrangement does not occur because the acylium ion is resonance stabilized. Thus, the acylium ion is much more stable than a carbocation. The lack of rearrangement of the carbon skeleton of the acyl group makes the Friedel-Crafts acylation a useful synthesis of alkyl benzenes. In addition, the acylation reaction does not bring about a second substitution reaction, whereas most alkylation reactions give significant di- and trisubstitution products. When chemists want to form a compound with a C 2 adjacent to the benzene ring, they first do an acylation reaction to form a ketone, then they reduce the carbonyl of the ketone to a C 2 group. This synthetic strategy is called an acylation-reduction sequence.

35 rganic Chemistry - Ch Daley & Daley RCCl CR reduce C 2 R AlCl 3 The Clemmensen reduction is a method used to convert the carbonyl group to a C 2 group. The most common reaction that chemists use to reduce the carbonyl group to an alkyl group is the Clemmensen reduction. A Clemmensen reduction reaction involves heating the ketone with a zinc-mercury amalgam in concentrated Cl. Many ketones that are stable in hot acids are reduced by the Clemmensen reduction. C 3 C 2 CCl AlCl 3 CC 2 C 3 Zn(g) Cl C 2 C 2 C 3 Propylbenzene (71% overall) The Wolff-Kishner reduction is another method used to convert the carbonyl group to a C 2 group. An alternative procedure to a Clemmensen reduction is the Wolff-Kishner reduction. The procedure for a Wolff-Kishner reduction involves heating the ketone with hydrazine ( 2 2 ) and potassium hydroxide in a high boiling alcohol solvent. The Wolff- Kishner reduction works with a variety of ketones and aldehydes that are stable in hot, concentrated base. (C 3 ) 3 CCCl AlCl 3 CC(C 3 ) 3 2 2, K Diethylene glycol reflux C 2 C(C 3 ) 3 (2,2-Dimethyl-1-propyl)benzene (76% overall) Both the Clemmensen reduction and the Wolff-Kishner reduction are very specific for reducing an aldehyde or a ketone to a methylene group. either reaction reduces the carbonyl group of carboxylic acid derivatives C π bonds. The choice between the two reduction processes depends on other groups present in the molecule. If there are acid sensitive functional groups, then use the Wolff- Kishner reaction. For base sensitive functional groups, use the Clemmensen reaction.

36 rganic Chemistry - Ch Daley & Daley Exercise Propose a synthesis for each of the following substituted aromatics. a) tert-butylbenzene b) 2-Methyl-1-phenylpropane c) Butylbenzene d) Toluene e) eopentylbenzene [PhC 2 C(C 3 ) 3 ] Sample solution c) C 3 C 2 C 2 CCl AlCl 3 CC 2 C 2 C 3 2 2, K Diethylene glycol reflux C 2 C 2 C 2 C 3 Synthesis of o-benzoylbenzoic Acid Phthalic anhydride AlCl 3 o-benzoylbenzoic acid (55%) To a dry 50 ml round-bottom flask, add 1.65 g (0.011 mol) of phthalic anhydride, 7 ml of dry benzene, and 3.4 g (0.025 mol) of anhydrous aluminum chloride. The apparatus must be dry because aluminum chloride reacts rapidly with water to release hydrogen chloride, thus, destroying the aluminum chloride. Fit the flask with a trap to collect the hydrogen chloride produced by the reaction. Stir at room temperature for 15 minutes. Warm to o C for 5-10 minutes then reflux for an hour. Cool the flask in an ice bath then add 15 g of crushed ice. ext, add concentrated hydrochloric acid until the solution clears (about 3 ml). Place the entire mixture in a 200 ml flask and distill until the distillate becomes clear. Cool the residue in the flask in ice, filter the product, and wash it with 5 ml of cold water. Dissolve the solid in 10 ml of 10% sodium carbonate. Filter any insoluble residue.

37 rganic Chemistry - Ch Daley & Daley Cautiously acidify with concentrated hydrochloric acid (until a p of 1-2 is reached), adding a little acid at a time with stirring. Continue stirring until any oil that separates becomes crystalline. The yield of the monohydrate of the acid is 2.7 g (55%), mp 94 o C (loses water). Discussion Questions 1. The Friedel-Crafts acylation does not work well with a carboxylic acid because an acylium ion cannot readily form from the acid. Explain why the acylium ion cannot readily form. 2. What is the purpose of dissolving the crude product in sodium carbonate solution? 18.9 Multiple Substituent Effects When a benzene ring has two or more substituents, all the substituents exert their combined effects on the reactivity of the ring and in the placement of any incoming electrophiles. In most cases, multiple substituents affect an electrophilic aromatic substitution reaction in one of the following four ways. 1) All available sites are equivalent. This means that a substitution at any one of these sites gives the same product. C 3 C 3 2 Fe C 3 All sites are equivalent C 3 2) All sites have comparable reactivity, but one site is more sterically hindered than the other. The reaction then takes place at the less sterically hindered site. Less sterically hindered C 3 C 3 2 Fe C(C 3 ) 3 C(C 3 ) 3 More sterically hindered