University:
Rutgers University Newark
Course:
CHEM 336 | Organic Chemistry ||
Academic year:

2024
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216

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78
Author:

Mahitab S.

CHAPTER 22 REACTIONS OF BENZENE AND ITS DERIVATIVES ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • (22.1) • (22.2) • (22.3) Electrophilic aromatic substitution Disubstitution and polysubstitution Nucleophilic aromatic substitution ©2018 Cengage Learning. All Rights Reserved. Substitution Reactions • The most characteristic reaction of aromatic compounds is substitution at a ring carbon • Following are some substitution reactions represented in the form of equations: 111 12 andbromonation Coloration 37 ©2018 Cengage Learning. All Rights Reserved. Substitution Reactions 141 5 161 ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution • Reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile, E+ • We study several common types of electrophiles, how each is generated, and the mechanism by which each replaces hydrogen on an aromatic ring ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Chlorination and Bromination • Step 1: Lewis acid-Lewis base reaction • Step 2: Make a new bond between a nucleophile and an electrophile (key step) ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Chlorination and Bromination • Step 3: Take a proton away (deprotonation) • Proton transfer regenerates the Lewis acid catalyst and gives chlorobenzene • Bromination: Treating benzene with bromine in the presence of ferric chloride or aluminum chloride gives bromobenzene and HBr Fed's ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - General Mechanism • General question - What is an electrophile and how is it generated? ©2018 Cengage Learning. All Rights Reserved. Figure 22.1 - Energy Diagram for the Reaction of Benzene with Bromine ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Nitration • Formation of the nitronium ion, NO2+ NI • Step 1: Add a proton (protonation) • Proton transfer from sulfuric acid to the OH group of nitric acid gives the conjugate acid of nitric acid • Step 2: Break a bond to give stable molecules or ions • Loss of H2O gives the nitronium ion, a very strong electrophile ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Nitration • (1) Resulting nitro group can be reduced to a 1° amino group, —NH2, by hydrogenation in the presence of a transition metal catalyst such as nickel, palladium, or platinum (H2, metal) Bpd Dpt • (2) A nitro group can be reduced to a 1° amino group by a metal in aqueous acid • Commonly used metal-reducing agents are iron, zinc, and tin in dilute HCl • Reductant is electrons from the metal (single electron transfer) ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Nitration • When reduced with a metal and HCl, the amine is obtained as a salt, which is then treated with strong base to liberate the free amine • Reduction is important because the amino group cannot be substituted directly onto an aromatic ring and must be done indirectly ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Sulfonation • Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide • Electrophile is either SO3 or HSO3+ depending on experimental conditions ©2018 Cengage Learning. All Rights Reserved. Example 22.1 - Nitration of Benzene • Write a stepwise mechanism for the nitration of benzene g p NE • Solution (next slide) • (1) The nitronium ion (a strong electrophile) is attacked by the benzene ring (a weak nucleophile) in Step 1 to give a resonancestabilized cation intermediate • (2) Proton transfer from this intermediate to either H2O or HSO4− in Step 2 regenerates the aromatic ring and gives nitrobenzene ©2018 Cengage Learning. All Rights Reserved. Example 22.1 - Nitration of Benzene • Step 1: Make a new bond between a nucleophile (arene ring) and an electrophile (key step) • Step 2: Take a proton away (deprotonation) hydronium generate ©2018 Cengage Learning. All Rights Reserved. Hot Electrophilic Aromatic Substitution - Friedel-Crafts Alkylation • Friedel-Crafts reactions: Hydrogen of an aromatic ring is replaced by an alkyl (alkylation) or acyl group (acylation) • One of the most important methods for forming new C—C bonds to aromatic rings c to Acyl hasoxygen atomattached withdoublebond 2 0 atoms Alkyl hasnooxygen alkyl carbonatom pond FidelReaction 4 1replaceringaromaticbyalkyl ore 2generate c ©2018 Cengage Learning. All Rights Reserved. c bond Electrophilic Aromatic Substitution - Friedel-Crafts Alkylation • Mechanism • Step 1: Lewis acid-Lewis base reaction • Step 2: Make a new bond between a nucleophile (arene ring) and an electrophile (key step) ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Alkylation • Step 3: Proton transfer regenerates the ring aromaticity Limitations 2 hybridized electrophiles: halogen atoms on sp2 • sp o hybridized carbons (vinylic and haloarenes) do NOT react to produce electrophiles under these conditions because high activation energy is required ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Alkylation • Limitations • Possibility for rearrangement of the alkyl group exists • For example, the isobutyl chloride/AlCl3 complex rearranges directly to the tert-butyl cation/AlCl4– ion pair, which is the electrophile in this example ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Alkylation • Alkylation fails on benzene rings bearing one or more strongly electron-withdrawing groups • It is hard to stop the reaction at monoalkylation because the alkylated product is more reactive than benzene itself ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Acylation • Reaction of an aromatic hydrocarbon with an acyl halide attached hasanoxygen bond double carbon to substitution involving • Electrophilic aromatic intramolecular acylation to form a six-membered ring is shown below: ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Acylation • Mechanism for the generation of an acylium ion • Step 1: Lewis acid-Lewis base reaction • Step 2: Break a bond to give stable molecules or ions, in this case an acylium ion (key step) ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Acylation • Two contributing structures can be drawn for an acylium ion • Acylium ions do not undergo rearrangement • Carbon skeleton of an acyl halide is transferred unchanged to the aromatic ring ©2018 Cengage Learning. All Rights Reserved. Example 22.2 - Friedel-Crafts Reactions • Write a structural formula for the product from FriedelCrafts alkylation or acylation of benzene for each compound ©2018 Cengage Learning. All Rights Reserved. Example 22.2 - Friedel-Crafts Reactions • Alkylation: (1) Benzyl chloride in the presence of a Lewis acid catalyst gives the benzyl cation (an electrophile), which is then attacked by benzene (a weak nucleophile), (2) followed by proton transfer to give diphenylmethane • In this example, the benzyl cation, although primary, cannot rearrange ©2018 Cengage Learning. All Rights Reserved. Example 22.2 - Friedel-Crafts Reactions • Acylation: Treating benzoyl chloride with aluminum chloride gives an acylium ion (an electrophile) • (1) Reaction of this cation with the π electrons of the aromatic ring (a weak nucleophile), (2) followed by proton transfer gives benzophenone ©2018 Cengage Learning. All Rights Reserved. Electrophilic Aromatic Substitution - Friedel-Crafts Acylation • A special value of Friedel-Crafts acylations is for the preparation of unrearranged alkylbenzenes • Example: Preparation of isobutylbenzene • (1) Treating benzene with 2-methylpropanoyl chloride in the presence of AlCl3 gives 2-methyl-1-phenyl-1-propanone • (2) Wolff-Kishner or Clemmensen reduction of the carbonyl group to a methylene group gives isobutylbenzene ©2018 Cengage Learning. All Rights Reserved. Other Electrophilic Aromatic Alkylations • Carbocations can be generated by: • Treating an alkene with a strong acid, most commonly HX, H2SO4, H3PO4, or HF/BF3 • Treating an alkene with a Lewis acid catalyst • Treating an alcohol with a strong acid, H2SO4, H3PO4, or HF ©2018 Cengage Learning. All Rights Reserved. Example (effects of substituents) In Bromination The productshould be inameta position • What is the major product of the reaction of 1,3 nitrobenzene with Br2/FeBr3? 7 Expo Br Br 1. 4 3 2 1 para 4. x 2. 3. i 32 1 meta ortho 5. x ©2018 Cengage Learning. All Rights Reserved. Example • Which structure is a major intermediate formed in the Ey electrophilic nitration of chlorobenzene? EN IT 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. I Example • What is the electrophile in the following aromatic substitution? Cl Y AlCl3 1. 2. 3. 4. ©2018 Cengage Learning. All Rights Reserved. 5. Example (effects of substituents) F L d • Fluorine is less deactivating than chlorine in the aromatic electrophilic substitution reactions • What is the main reason for this reactivity trend? 1. 2. 3. 4. 5. Fluorine forms stronger π bonds than chlorine, providing more resonance stabilization Chlorine is more electronegative than fluorine x Because of its size, chlorine has stronger inductive influence than fluorine x Fluorine is smaller, making the entry of electrophiles easier x Chlorine forms complexes with electrophiles, diminishing their reactivity x ©2018 Cengage Learning. All Rights Reserved. Example • Which one is not a limitation of Friedel-Crafts alkylations? 1. 2. 3. 4. 5. Carbocation rearrangements may occur Polyalkylation products are possible Only substrates with selected activating groups can be used Vinyl halides cannot be used to generate electrophiles The halogen in the aluminum halide must match the one in the alkyl halide i ©2018 Cengage Learning. All Rights Reserved. Example (effects of substituents) In Bromination The productshould be in a meta pas • What is the major product of the following reaction? I CH3 HOOC 1. X 2. X is xi 4. Br2 FeBr3 3. e 5. ©2018 Cengage Learning. All Rights Reserved. ie Example • Which of the following is not a practical method to generate an electrophile for aromatic substitution reaction? 1. 2. 3. 4. 5. HNO3/H2SO4 Cl2/FeBr3 I2/CuCl2 SO3/H2SO4 CH3COCl/AlBr3 41412023 ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Effects of a Substituent Group on Further Substitution • In electrophilic aromatic substitution of a monosubstituted benzene, the new group may become oriented ortho, meta, or para to the existing group • Generalizations on the manner in which existing groups influence further substitution reactions • (1) Substituents affect the orientation of new groups • (2) Classified as either ortho/para directing or meta directing (important) • (3) Certain substituents cause the rate of a second substitution to be greater than that for benzene itself, whereas others cause the rate to be lower than that for benzene • (4) Substituents are classified as activating or deactivating toward further substitution (important) ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Effects of a Substituent Group on Further Substitution anisole OME • Example: Nitration of anisole (OMe = EDG) • (1) proceeds at a rate considerably greater than that for benzene (the methoxy group is activating) • (2) Product is a mixture of o-nitroanisole and pnitroanisole (the methoxy group is ortho/para directing) ortho ©2018 Cengage Learning. All Rights Reserved. para Disubstitution and Polysubstitution - Effects of a Substituent Group on Further Substitution • Example: Nitration of benzoic acid (CO2H = EWG) • Product formed in the nitration of benzoic acid consists of approximately 80% of the meta isomer and 20% of the ortho and para isomers combined • The carboxyl group is meta directing Mptajor ©2018 Cengage Learning. All Rights Reserved. Table 22.2 - Directing Effects of Substituents on Further Substitution (important) apology CH3 Toulene ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Effects of a Substituent Group on Further Substitution • From the information in Table 22.2, one can make the following generalizations: • (1) Alkyl groups, phenyl groups, and substituents in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing (alkyl, Ph, OR, NR, SR, X) • (2) All other substituents are meta directing (COR, CN, SO2R, NO2, CF3, NH3+) • (3) All ortho-para directing groups except the halogens are activating toward further substitution • (4) The halogens are weakly deactivating ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Effects of a Substituent Group on Further Substitution • Example: Conversion of toluene to p-nitrobenzoic acid • The order in which the reactions are performed is critical ©2018 Cengage Learning. All Rights Reserved. Example 22.4 - Electrophilic Aromatic Substitution: Directing Effects • Complete these electrophilic aromatic substitution reactions • Where you predict meta substitution, show only the meta product • Where you predict ortho-para substitution, show both products a Ogata LY meta IT So É ©2018 Cengage Learning. All Rights Reserved. no Example 22.4 - Electrophilic Aromatic Substitution: Directing Effects • Bromine is (1) ortho-para directing, and (2) weakly deactivating • The sulfonic acid group is (1) meta directing, and (2) moderately deactivating ©2018 Cengage Learning. All Rights Reserved. Table 22.1 - Orientation on Nitration of Monosubstituted Benzenes ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Directing Effects Themoststabletransitionstate Thefastesttheratedeterminestep TheOverallReaction • The slow and rate-determining step is attack of the electrophile by the aromatic ring • Rate of the step depends on the stability of the transition state for the step • The more stable the transition state, the faster the ratedetermining step and thus the overall reaction • (1) For ortho-para directors, ortho-para attack forms a more stable cation than meta attack • Ortho-para products are formed faster than meta products • (2) For meta directors, meta attack forms a more stable cation than ortho-para attack • Meta products are formed faster than ortho-para products ©2018 Cengage Learning. All Rights Reserved. Figure 22.2 - Nitration of Anisole • Electrophilic attack meta and para to the methoxy group ©2018 Cengage Learning. All Rights Reserved. Figure 22.3 - Nitration of Benzoic Acid • Electrophilic attack meta and para to the carboxyl group ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Directing Effects • Almost all the ortho-para directing groups have an unshared pair of electrons on the atom bonded to the aromatic ring • Directing effect is attributable to a resonance effect, due to the ability of the atom bonded to the ring to further delocalize the positive charge of the cation intermediate formed when electrophilic attack occurs at the ortho or para positions a • Inductive effect of alkyl groups on stability of the cation intermediate should be considered to account for the fact that they are also ortho-para directing • Inductive polarization of electrons from the alkyl group to the cationic ring of the intermediate equals further delocalization of the positive charge, thus stabilizing the intermediate ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Directing Effects • Alkyl groups are activating because the cationic intermediates are lower in energy with alkyl substituents at ortho or para positions • Delocalization due to inductive polarization is effective when the alkyl group is bonded directly to the ring atom carrying significant positive charge ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Activating-Deactivating Effects • (1) Any resonance effect, such as that of —NH2, —OH, and — OR, that delocalizes the positive charge of the cation intermediate lowers the activation energy for its formation and has an activating effect toward further EAS • (2) Any resonance or inductive effect, such as that of —NO2, —C≡N, —C=O, —SO2—, and —SO3H, that decreases electron density on the ring deactivates the ring to further substitution ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Activating-Deactivating Effects • (3) Any inductive effect, such as that of —CH3 or another alkyl group, that releases electron density toward the cationic intermediate activates the ring toward further substitution • (4) Any inductive effect, such as that of halogen, —NR3+, — CCl3, or —CF3, that decreases electron density on the ring deactivates the ring to further substitution decreaseelectrondensity effect Inductive Nitrosogroup ortho para deactive ©2018 Cengage Learning. All Rights Reserved. Disubstitution and Polysubstitution - Theory of Activating-Deactivating Effects • For halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger • The net effect is that halogens are (1) weakly deactivating but (2) ortho-para directing • For cases involving EAS of aromatic rings with two or more substituents already on the ring, the more activating group will dominate the orientation preference of the incoming group • Ortho-para directing groups will dominate meta directing groups when they are both on a ring ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following compounds would react fastest with HNO3/H2SO4? 1. 2. 3. 4. 5. Nitrobenzene (PhNO2) Toluene (PhCH3) Bromobenzene (PhBr) Anisole (PhOCH3) Benzoic acid (PhCOOH) ©2018 Cengage Learning. All Rights Reserved. Example • Which series of reactions will convert benzene into portho para nitrobenzoic acid? 1. 2. 3. 4. 5. CH3Br/AlBr3 followed by HNO3/H2SO4, followed by KMnO4/H2O HNO3/H2SO4 followed by KMnO4/H2O, followed by CH3Br/AlBr3 KMnO4/H2O followed by CH3Br/FeBr3, followed by HNO3/H2SO4 CH3Br/AlBr3 followed by KMnO4/H2O, followed by HNO3/H2SO4 HNO3/H2SO4 followed by CH3Br/AlBr3, followed by KMnO4/H2O ©2018 Cengage Learning. All Rights Reserved. Example r • What would be the main product of nitration of benzenesulfonic acid? Meta 1. 2. 3. 4. 5. o-Nitrobenzenesulfonic acid p-Nitrobenzenesulfonic acid 2-Nitrobenzoic acid m-Nitrobenzenesulfonic acid m-Nitrobenzoic acid ©2018 Cengage Learning. All Rights Reserved. Example • Based on the electronic structure, what kind of substituent effect would you expect from the nitroso group? N O 1. 2. x3. 4. x o,p-Directing, deactivating o,p-Directing, activating m-Directing, activating m-Directing, deactivating nitroso group b ortho para ©2018 Cengage Learning. All Rights Reserved. Example (SNAr, addition-elimination) • Which of the following represents the intermediate formed in the reaction between p-chloronitrobenzene and hydroxide ion? 1. 2. 3. 4. F 5. to it ortho para ©2018 Cengage Learning. All Rights Reserved. Example (benzyne, elimination-addition) • What is the result of the reaction between mbromotoluene and sodium amide? NaNH2 O Br 1. 2. 3. 4. 5. 2-Aminotoluene 3-Aminotoluene 4-Aminotoluene All of the answers None of the answers b NH3(l) ortho para It ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution • Reaction in which most commonly a halogen on an aromatic ring is replaced by another nucleophile (example on the next slide) • Haloarenes (Ar-X) do NOT undergo substitution by either of the SN1 or SN2 pathways • Haloarenes (Ar-X) undergo nucleophilic aromatic substitution under certain conditions, but by mechanisms quite different from those for nucleophilic aliphatic substitution • Far less common than electrophilic aromatic substitutions and has limited application for the synthesis of organic compounds ©2018 Cengage Learning. All Rights Reserved. l Nucleophilic Aromatic Substitution - Benzyne Intermediate • Example: when heated at 300°C under high pressure with aq NaOH, chlorobenzene is converted to sodium phenoxide • Neutralization of the salt with aqueous acid gives phenol • o-chlorotoluene in similar conditions gives a mixture of 2methylphenol and 3-methylphenol ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution - Benzyne Intermediate • The same type of reaction can be brought about using sodium amide in liquid ammonia • Entering group appears not only at the position occupied by the leaving group but also at a position adjacent to it ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution - Benzyne Intermediate • Mechanism • Step 1: Take a proton away and simultaneously break a bond to make stable molecules or ions (key step) • De-hydro-halogenation of the benzene ring gives a benzyne intermediate • Step 2: Make a new bond between a nucleophile and an electrophile ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution - Benzyne Intermediate • Step 3: Add a proton • Proton transfer from NH3 to the carbanion intermediate gives one of the observed substitution products and generates a new amide ion ©2018 Cengage Learning. All Rights Reserved. Benzyne Intermediate • According to molecular orbital theory, the benzene ring retains its planarity, p bonding, and aromatic character • Relatively high energy of the benzyne intermediate is presumably why such high temperatures are required for reactions such as de-hydro-halogenation CH3 CH3 NaNH 2 Cl H b-elimination A benzyne intermediate ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution Addition/Elimination • When an aromatic compound contains strong electronwithdrawing nitro groups ortho and/or para to halogen, nucleophilic aromatic substitution takes place readily • Example: Heating 1-chloro-2,4-dinitrobenzene at reflux in aq sodium carbonate followed by treatment with aqueous acid yields 2,4-dinitrophenol ©2018 Cengage Learning. All Rights Reserved. Nucleophilic Aromatic Substitution Addition/Elimination • Step 1: Make a new bond between a nucleophile and an electrophile (key step) • Step 2: Break a bond to give stable molecules and ions ©2018 Cengage Learning. All Rights Reserved. Example 22.6 - Nucleophilic Aromatic Substitution • What is the state of hybridization of each ring carbon atom in the Meisenheimer complex shown below? • Solution • The carbon atom bonded to both the leaving group and entering nucleophile (—Cl and —Nu in the structure shown) is sp3 hybridized • The other five carbons of the ring are sp2 hybridized ©2018 Cengage Learning. All Rights Reserved. Example • Select the major product of the following reaction KMnO4 H2O 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Example • What is the best sequence of reactions to synthesize the desired product (Pr = propyl)? Pr 1 2 3 Mata 1,2 NH 2 E o 8 ©2018 Cengage Learning. All Rights Reserved. Example • What are the reagents necessary for Step 3 in the following transformation? 1 2 3 SO3H 1. 2. 3. 4. 5. CH3COCl/AlCl3 CH3CH2Br/AlBr3 SO3/H2SO4 H2/Pd SOCl2/AlCl3 ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following carbons of the benzyl radical has the smallest unpaired electron density? H 1 H 5 2 3 1. 2. 3. 4. 5. 1 2 3 4 5 4 ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation • When certain aromatic compounds are treated with formaldehyde (CH2O), and HCl, the CH2Cl group is introduced onto the ring • This reaction is known as chloromethylation • Propose a mechanism for this example of chloromethylation ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation • The most likely mechanism involves an acid-catalyzed electrophilic aromatic substitution followed by replacement of the resulting —OH group with Cl via a benzylic cation intermediate ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation • Step 2: Make a new bond between a nucleophile (p bond) and an electrophile ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation ©2018 Cengage Learning. All Rights Reserved. Problem 22.48 - Chloromethylation ©2018 Cengage Learning. All Rights Reserved.