Electrophilic Aromatic Substitution Reactions PDF

Electrophilic Aromatic Substitution Reactions The most common reaction of aromatic compounds is electrophilic aromatic substitution, a process in which an electrophile (E) reacts with an aromatic ring and substitutes for one of the hydrogens. Many different substituents can be introduced onto...

Electrophilic Aromatic Substitution Reactions The most common reaction of aromatic compounds is electrophilic aromatic substitution, a process in which an electrophile (E) reacts with an aromatic ring and substitutes for one of the hydrogens. Many different substituents can be introduced onto the aromatic ring by electrophilic substitution.  To list some possibilities, an aromatic ring can be substituted by a halogen ( - Cl, -Br, -I), a nitro group ( -NO2), a sulfonic acid group ( -SO3H), an alkyl group (R), or an acyl group ( -COR). Starting from only a few simple materials, it’s possible to prepare many thousands of substituted aromatic compounds (Figure 5.2). Mechanism of Electrophilic Aromatic Substitution Chapter 17 3  Bromination of Benzene Bromine does not react with benzene at room temperature. For bromination of benzene to take place, a catalyst such as FeBr3 is needed. The catalyst makes the Br2 molecule more electrophilic by reacting with it to give FeBr4- and Br+. The electrophilic Br+ then reacts with the electron-rich (nucleophilic) benzene ring to yield a carbocation intermediate that is not aromatic. This carbocation is doubly allylic and is a hybrid of three resonance forms Mechanism for the Bromination of Benzene: Step 1 + - Br Br FeBr3 Br Br FeBr3 (stronger electrophile than Br2) Before the electrophilic aromatic substitution can take place, the electrophile must be activated. A strong Lewis acid catalyst, such as FeBr3, should be used. Chapter 17 5 Mechanism for the Bromination of Benzene: Steps 2 and 3 Step 2: Electrophilic attack and formation of the sigma complex. H H H H H H Br Br FeBr3 Br + FeBr4- H H H H H H Step 3: Loss of a proton to give the products. H H H FeBr4- H H Br Br + FeBr3 + HBr H H H H H H Chapter 17 6  Nitration of Benzene NO2 HNO3 H2SO4 + H2O Aromatic rings are nitrated by reaction with a mixture of concentrated nitric and sulfuric acids. This produces the electrophile of the reaction: nitronium ion (NO2+). Sulfuric acid acts as a catalyst, allowing the reaction to be faster and at lower temperatures. Chapter 17 7  Reduction of the Nitro Group NO2 NH2 Zn, Sn, or Fe aq. HCl Aromatic nitration does not occur in nature; but it is particularly important in the laboratory because the nitro-substituted product can be reduced by reagents such as iron, tin (Sn), or SnCl2 to yield an amino-substituted product, or arylamine, ArNH2. This is the best method for adding an amino group to the ring in the industrial synthesis of many dyes and pharmaceutical agents. Chapter 17 8  Sulfonation of Benzene SO3H H2SO4 + SO3 Aromatic rings are sulfonated by reaction with fuming sulfuric acid (a 7% mixture of SO3 and H2SO4). The reactive electrophile is HSO3 , and substitution occurs by the usual two-step mechanism seen for bromination. The —SO3H group is called a sulfonic acid. Aromatic sulfonation is a key step in the synthesis of such compounds as the sulfa drug family of antibiotics Chapter 17 9  Desulfonation Reaction SO3H + H H , heat + H2O + H2SO4 Sulfonation is reversible. The sulfonic acid group may be removed from an aromatic ring by heating in dilute sulfuric acid. In practice, steam is often used as a source of both water and heat for desulfonation. Chapter 17 10  Nitration of Toluene Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and para substituted molecules. Chapter 17 11  The Friedel–Crafts Alkylation and Acylation Reactions One of the most useful electrophilic aromatic substitution reactions is alkylation—the introduction of an alkyl group onto the benzene ring. Called the Friedel–Crafts alkylation reaction after its discoverers, the reaction is carried out by treating the aromatic compound with an alkyl chloride, RCl, in the presence of AlCl3to generate a carbocation electrophile, R+. Aluminum chloride catalyzes the reaction by helping the alkyl halide to dissociate in much the same way that FeBr3catalyzes aromatic brominations by helping Br2dissociate. Loss of H+ then completes the reaction  Closely related to the Friedel–Crafts alkylation reaction is the Friedel– Crafts acylation reaction. When an aromatic compound is treated with a carboxylic acid chloride (RCOCl) in the presence of AlCl3, an acyl (a-sil) group(R-C=O) is introduced onto the ring. For example, reaction of benzene with acetyl chloride yields the ketone acetophenone. Mechanism of the Friedel–Crafts Reaction  Limitations of Friedel–Crafts F-C reactions works only with benzene, activated benzene derivatives and halobenzene. Reaction fails on aromatic rings that are strongly deactivated (-NO2, -CN,-SO3H, or -COR.) Such aromatic rings are much less reactive than benzene. Like other carbocation reactions, the F-C alkylation is susceptible to carbocation rearrangements. The alkylbenzene product formed is more reactive than benzene, so multiple alkylation (polyalkylation) occurs. Chapter 17 15  Clemmensen Reduction The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc. Chapter 17 16  Substituent Effects in Electrophilic Aromatic Substitution Substituents affect both the reactivity of an aromatic ring and the orientation of a reaction. Substituents affect the reactivity of an aromatic ring Some substituents activate a ring, making it more reactive than benzene, others deactivate a ring, making it less reactive than benzene. In aromatic nitration, for instance, the presence of an OH substituent makes the ring 1000 times more reactive than benzene, while an NO2 substituent makes the ring more than 10 million times less reactive Activators Deactivators  Substituents affect the orientation of a reaction The three possible disubstituted products—ortho, meta, and para— are usually not formed in equal amounts. Instead, the nature of the substituent already present on the ring determines the position of the second substitution. An OH group directs further substitution toward the ortho and para positions, for instance, while a CN directs further substitution primarily toward the meta position.  Effect of Multiple Substituents Two or more substituents exert a combined effect on the reactivity of an aromatic ring. If the groups reinforce each other, the result is easy to predict. For example in dimethylbenzene (Xylene), both methyl groups are activating, and in nitrobenzoic acid, both substituents are deactivating. When the directing effects of two or more substituents conflict, it is more difficult to predict where an E+ will react. In many cases a mixture will result. Activating groups are usually stronger directors than deactivating groups.  Effect of Multiple Substituents OCH3 OCH3 OCH3 Br Br2 FeBr3 O2N O2N O2N Br If directing effects oppose each other, the most powerful activating group has the dominant influence. The directing effect of the two (or more) groups may reinforce each other. All activating groups are ortho and para-directing, and all deactivating groups other than halogen are meta-directing. The halogens are unique in being deactivating but ortho- and para- directing.  Oxidation and Reduction of Aromatic compounds CH2CH3 CO2H KMnO4, NaOH H2O, 100oC (or Na2Cr2O7, H2SO4 , heat) Despite its unsaturation, a benzene ring does not usually react with strong oxidizing agents such as KMnO4 Alkyl groups attached to the aromatic ring are readily attacked by oxidizing agents, and are converted into carboxyl groups ( CO2H). For example, Ethylbenzene is oxidized by KMnO4 to give benzoic acid.  Nitration of Toluene Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and para substituted molecules. Chapter 17 25  Alkyl Group Stabilization CH2CH3 CH2CH3 CH2CH3 CH2CH3 Br Br2 FeBr3 + + Br Br o-bromo m-bromo p-bromo (38%) (< 1%) (62%) Alkyl groups are activating substituents and ortho, para- directors. This effect is called the inductive effect because alkyl groups can donate electron density to the ring through the sigma bond, making them more active. Chapter 17 26 Review on Electrophilic aromatic substitution (EAS). What have we learned? The aromatic ring acts as a nucleophile, and attacks an added electrophile E An electron-deficient carbocation intermediate is formed (the rate- determining step) which is then deprotonated to restore aromaticity Electron-donating groups on the aromatic ring (such as OH, OCH3, and alkyl) make the reaction faster, since they help to stabilize the electron- poor carbocation intermediate Electron withdrawing groups on the aromatic ring (such as NO2, SO3H and CN makes the reaction slower) Lewis acids can make electrophiles even more electron-poor (reactive), increasing the reaction rate. For example FeBr3 / Br2 allows bromination to occur at a useful rate on benzene, whereas Br2 by itself is slow).  Nucleophilic Aromatic substitution What is Nucleophilic Aromatic Substitution (NAS)? How does NAS differ from Electrophilic Aromatic Substitution (EAS)? Why does NAS tend to work best with electron-poor aromatics and excellent nucleophiles? Finally, how does it work?  How does Nucleophilic Aromatic substitution differ from Electrophilic Aromatic Substitution? In Nucleophilic Aromatic substitution reaction, The species that attacks the ring is a nucleophile, not an electrophile The aromatic ring is electron-poor (electrophilic), not electron rich (nucleophilic) The “leaving group” is chlorine, not H+ The position where the nucleophile attacks is determined by where the leaving group is, not by electronic and steric factors (i.e. no mix of ortho– and para- products as with electrophilic aromatic substitution). To be precise, the roles of the aromatic ring and attacking species are reversed!  In NAS, electron withdrawing groups (EWG’s) dramatically increase the rate of reaction, not decrease it. electrophilic aromatic substitution operate, but in reverse. Unlike in electrophilic aromatic substitution, there are no “ortho- ,para-” or “meta-” directors. The position of substitution is controlled by the placement of the leaving group.