Chapter 21: Electrophilic Aromatic Substitution

1. Introduction: Enols and Phenols

• Enols and Ketones: Many ketones exist in equilibrium with their enol tautomers, which are nucleophilic. This enolization is catalyzed by acid or base. For instance, pentan-3-one undergoes deuteration at its α-protons in acidic D2​O via its enol form.
• Phenols as Stable Enols: Phenol is a highly stable enol due to the aromaticity of its benzene ring. Its proton NMR spectrum shows protons at the 2, 4, and 6 positions (ortho and para) being replaced by deuterium when shaken with acidic D2​O. This process is electrophilic substitution, characteristic of aromatic compounds.

2. Benzene and its Reactions with Electrophiles

• Structure of Benzene: Benzene is a planar, symmetrical hexagon with six trigonal (sp2) carbon atoms, each bearing one hydrogen atom in the plane of the ring. All bond lengths are equal (≈1.39A˚), indicating delocalization.
• Aromaticity: The special stability of benzene comes from its six π electrons in three molecular orbitals, leading to exceptional stability and a characteristic ring current observed in NMR.
• Reactivity Compared to Alkenes: Simple alkenes (e.g., cyclohexene) react readily with electrophiles via addition. Benzene, however, is much less reactive and typically undergoes substitution rather than addition with electrophiles, as this preserves its aromaticity. It requires highly reactive (often cationic) electrophiles and a Lewis acid catalyst for reactions like bromination.
• General Mechanism of Electrophilic Aromatic Substitution (EAS):
  1. Attack by Electrophile (E+): The aromatic ring acts as a nucleophile, attacking the electrophile. This step is rate-determining and leads to an unstable, delocalized cationic intermediate (a σ-complex or arenium ion). This intermediate is not aromatic as it contains an sp3-hybridized carbon atom within the ring.
  2. Loss of Proton: A proton is rapidly lost from the sp3 carbon, restoring the aromaticity of the ring and forming the substituted product.
  • Evidence for Cationic Intermediate: In strong acids, the protonated aromatic compound (the cationic intermediate) can be observed by NMR at very low temperatures.

3. Specific Electrophilic Aromatic Substitution Reactions of Benzene

• Nitration:
  • Reagents: Concentrated HNO3​ and H2​SO4​.
  • Electrophile: Nitronium ion (NO2+​), generated by protonation of nitric acid by sulfuric acid followed by loss of water.
  • Product: Nitrobenzene (ArNO2​).
  • Note: The nitronium ion is linear (sp-hybridized nitrogen).
• Sulfonation:
  • Reagents: Concentrated H2​SO4​ or oleum (H2​SO4​+SO3​).
  • Electrophile: SO3​ or SO3​H+.
  • Product: Benzenesulfonic acid (ArSO2​OH).
  • Note: Sulfonic acids are strong acids. This reaction is reversible, and the product can be isolated as its sodium salt.
• Friedel-Crafts Alkylation:
  • Reagents: Tertiary alkyl halide (RX) and a Lewis acid (e.g., AlCl3​).
  • Electrophile: Carbocation (R+), generated by the Lewis acid removing the halide from the alkyl halide.
  • Product: Alkylbenzene (ArR).
  • Problems:
    1. Multiple Substitutions: The alkyl group is an activating substituent, making the product more reactive than benzene, leading to polysubstitution.
    2. Rearrangements: Primary and secondary carbocations can rearrange to more stable tertiary carbocations, leading to mixtures of products.
• Friedel-Crafts Acylation:
  • Reagents: Acid chloride (RCOCl) or anhydride ((RCO)2​O) and a Lewis acid (e.g., AlCl3​).
  • Electrophile: Acylium ion (RCO+), which is stabilized by resonance with the adjacent oxygen lone pair.
  • Product: Aryl ketone (ArCOR).
  • Advantages over Alkylation:
    1. Single Substitution: The acyl group is deactivating, so the product is less reactive than the starting material, preventing polysubstitution.
    2. No Rearrangements: The acylium ion is resonance-stabilized, so rearrangements are not an issue.
    3. Synthesis of n-Alkylbenzenes: The ketone product can be reduced (e.g., Clemmensen reduction: Zn/Hg, HCl) to yield an n-alkylbenzene cleanly, which is difficult via direct alkylation.

4. Directing Effects of Substituents on Benzene Ring Reactivity and Regioselectivity

Substituents on a benzene ring influence both the rate of electrophilic substitution and the position (regioselectivity) where the new electrophile attaches.

• Activating Groups (Ortho, Para-Directing): These groups increase the electron density of the benzene ring, making it more reactive towards electrophiles. They direct the incoming electrophile to the ortho and para positions relative to themselves.
  • Strongly Activating (Lone Pair Donation): Groups with lone pairs directly attached to the ring. These donate electrons by resonance, increasing electron density primarily at ortho and para positions.
    • Examples: −NH2​, −NHR, −NR2​ (anilines), −OH (phenols), −OR (anisoles).
    • Anilines: Extremely activating, often leading to polysubstitution (e.g., with Br2​). To control reactivity, anilines can be converted to less reactive amide derivatives (anilides) by acylation, which then undergo mono-substitution, primarily at the para position due to steric hindrance and inductive effects. The amide can then be hydrolyzed back to the amine.
    • Phenols: Also highly activating and react rapidly without a catalyst. Direct mainly to para, but ortho products are also formed. To favor mono-substitution, use specific conditions (e.g., CS2​ at low temperature for bromination).
  • Weakly Activating (Inductive/Hyperconjugation): Alkyl groups. They donate electrons by hyperconjugation (σ-conjugation) and inductive effect.
    • Examples: −CH3​, −R (toluene, alkylbenzenes).
    • Direct to ortho and para. Toluene reacts faster than benzene. The positive charge in the intermediate is stabilized when the electrophile attacks ortho or para, leading to a tertiary-like carbocation.
• Deactivating Groups (Meta-Directing): These groups withdraw electron density from the benzene ring, making it less reactive towards electrophiles. They direct the incoming electrophile to the meta position.
  • Strongly Deactivating (Resonance Withdrawal): Groups with a π bond to an electronegative atom directly attached to the ring. They withdraw electrons by resonance, particularly from the ortho and para positions, leaving the meta positions relatively richer in electron density.
    • Examples: −NO2​ (nitrobenzene), −CN (benzonitrile), −COR (acylbenzenes/ketones, aldehydes, esters), −SO3​H (sulfonic acids).
    • These groups make the ring significantly less reactive. For instance, nitration of nitrobenzene requires harsher conditions, and the second nitro group goes meta.
• Halogens (Deactivating, Ortho, Para-Directing): Halogens are unique because they are electronegative and withdraw electrons inductively (deactivating effect), but they also have lone pairs that can donate electrons by resonance (activating effect). The inductive effect is generally stronger than the resonance effect, making halobenzenes less reactive than benzene. However, the resonance effect directs to the ortho and para positions.
  • Examples: −F, −Cl, −Br, −I.
  • F is the most electronegative but its 2p orbital overlaps well with carbon’s 2p orbital, so it can be less deactivating or even activating in some cases (e.g., proton exchange, acetylation).
  • Cl, Br, I have poorer p-orbital overlap due to size mismatch, making them more deactivating.
  • Ortho/para ratio can be influenced by steric hindrance (larger halogens prefer para) and the inductive effect (stronger inductive effect on F and Cl disfavors ortho).

5. Two or More Substituents: Cooperation and Competition

• Cooperation: If multiple substituents direct to the same positions, they cooperate to enhance selectivity.
  • Example: p-hydroxybenzaldehyde, where the aldehyde directs meta and the OH directs ortho, both favoring the same positions for incoming electrophile.
• Competition: If substituents direct to different positions, the more activating group usually dominates the directing effect. Activating effects generally outweigh deactivating effects. Steric factors also play a role, especially for ortho substitution.

6. Exploiting the Chemistry of the Nitro Group

• Introduction of Nitro Group: Easy via nitration.
• Reduction to Amino Group: Nitro groups can be readily reduced to amino groups (e.g., Sn/HCl or H2​/Pd-C). This is crucial because it converts a meta-directing group into a powerful ortho, para-directing group.
• Diazonium Chemistry: The amino group can be further converted into a diazonium salt (ArN2+​), which is unstable and readily loses nitrogen gas (N2​), allowing for the replacement of the nitrogen substituent with a wide range of other groups (OH, CN, Br, I, etc.) through nucleophilic aromatic substitution (discussed further in Chapter 22). This provides powerful synthetic versatility for creating diverse aromatic compounds.

7. Regioselectivity and Ortholithiation (Chapter 24 Sneak Peek)

• Controlling Ortho Selectivity: While electron-donating groups often give ortho/para mixtures, specific methods can enforce ortho-selectivity.
  • Metallation (Ortholithiation): Using strong bases like butyllithium, a directed metallation can occur ortho to a directing group (e.g., OMe, NR2​), followed by reaction with an electrophile. This is particularly useful for introducing substituents that are otherwise difficult to install with ortho selectivity.

Multiple Choice Questions (MCQ) on Electrophilic Aromatic Substitution

Instructions: Choose the best answer for each question.

1. Which of the following best describes the stability of phenol’s enol form? a) It is unstable and readily reverts to the keto form. b) It is stabilized by conjugation with a carbonyl group. c) It is highly stable due to the aromaticity of its benzene ring. d) It only exists in the presence of strong bases.

2. What is the approximate bond length of C-C bonds in benzene? a) 1.54A˚ b) 1.33A˚ c) 1.39A˚ d) 1.20A˚

3. Why does benzene primarily undergo substitution reactions rather than addition reactions with electrophiles? a) Because substitution reactions are kinetically favored. b) Because addition reactions would disrupt its aromaticity. c) Because benzene is a strong nucleophile. d) Because electrophiles are typically too large to add to benzene.

4. What is the rate-determining step in electrophilic aromatic substitution? a) Loss of a proton from the intermediate. b) Attack by the electrophile to form the cationic intermediate. c) Rearrangement of the carbocation. d) Formation of the leaving group.

5. What is the common name for the cationic intermediate formed during electrophilic aromatic substitution? a) Benzyl cation b) Phenyl radical c) Arenium ion (σ-complex) d) Allyl cation

6. Which of the following is the electrophile for the nitration of benzene? a) NO3−​ b) HNO2​ c) NO2+​ d) N2​O4​

7. Which acids are typically used for the nitration of benzene? a) HCl and H2​SO4​ b) H3​PO4​ and HNO3​ c) Concentrated HNO3​ and H2​SO4​ d) CH3​COOH and HNO3​

8. What is oleum used for in sulfonation reactions? a) To neutralize the product acid. b) To generate the SO3​ electrophile. c) To act as a solvent only. d) To remove water from the reaction mixture.

9. Which of the following is a disadvantage of Friedel-Crafts alkylation? a) It requires very high temperatures. b) It only works with primary alkyl halides. c) It often leads to multiple substitutions and carbocation rearrangements. d) It produces unwanted by-products that are difficult to remove.

10. What type of carbocation is typically formed in Friedel-Crafts alkylation that can lead to rearrangements? a) Primary b) Secondary c) Tertiary d) Both primary and secondary

11. What is the electrophile in Friedel-Crafts acylation? a) Carbocation (R+) b) Acyl radical (RCO⋅) c) Acylium ion (RCO+) d) Acyl anion (RCO−)

12. Why is Friedel-Crafts acylation generally preferred over Friedel-Crafts alkylation for synthesizing alkylbenzenes? a) Acylation is faster. b) Acylation products are more reactive, promoting further reactions. c) Acylation introduces a deactivating group, preventing polysubstitution, and the product can be reduced to an alkylbenzene. d) Acylation requires less expensive reagents.

13. Which of the following groups is considered a strongly activating ortho, para-director? a) −NO2​ b) −CH3​ c) −Cl d) −OH

14. What is the primary reason that −NH2​ groups are powerful activating groups? a) Their inductive electron-withdrawing effect. b) Their ability to accept a proton. c) Their resonance electron-donating effect via a lone pair. d) Their steric hindrance.

15. To control the polysubstitution of aniline during bromination, what derivative can be formed? a) Nitrobenzene b) Acetanilide (amide derivative) c) Phenyl acetate d) Aniline hydrochloride

16. How do alkyl groups (e.g., −CH3​) activate the benzene ring towards electrophilic attack? a) By withdrawing electrons inductively. b) By resonance donation of a lone pair. c) By hyperconjugation (σ-conjugation) and inductive effect. d) By steric hindrance.

17. Which positions are primarily activated by an alkyl group on a benzene ring? a) Meta b) Ortho and para c) Only ortho d) Only para

18. Which of the following groups is considered a strongly deactivating meta-director? a) −NH2​ b) −OCH3​ c) −CHO (aldehyde) d) −Br

19. What is the main reason that a nitro group (NO2​) is a meta-director? a) It donates electrons inductively to the meta position. b) It withdraws electrons by resonance, primarily from the ortho and para positions. c) It is sterically hindering, forcing substitution to the meta position. d) It is a strong oxidizing agent.

20. Halogens are unique in their directing effects because they are: a) Activating and meta-directing. b) Deactivating and meta-directing. c) Activating and ortho, para-directing. d) Deactivating and ortho, para-directing.

21. What is the primary reason halogens are deactivating towards electrophilic aromatic substitution? a) Their resonance electron-donating effect. b) Their strong inductive electron-withdrawing effect. c) Their large atomic size. d) Their ability to form stable complexes.

22. Among the halogens, which one generally exhibits the best p-orbital overlap for resonance donation with the carbon 2p orbitals? a) Iodine b) Bromine c) Chlorine d) Fluorine

23. If two substituents on a benzene ring direct an incoming electrophile to different positions, which group’s directing effect usually dominates? a) The larger group. b) The more activating group. c) The group that is meta to the incoming electrophile. d) The group with the highest atomic number.

24. The transformation of an aromatic nitro group (NO2​) into an amino group (NH2​) is typically achieved by what type of reaction? a) Oxidation b) Hydrolysis c) Reduction d) Alkylation

25. Why is the reduction of a nitro group to an amino group a synthetically important transformation? a) It makes the ring less reactive. b) It changes a meta-directing group into an ortho, para-directing group. c) It introduces a halogen atom. d) It prevents further reactions.

26. What is diazonium chemistry used for in the context of electrophilic aromatic substitution? a) To introduce nitro groups. b) To reduce amino groups. c) To replace amino groups with various other substituents. d) To activate the benzene ring for addition reactions.

27. What is ortholithiation a method for? a) Introducing a meta-directing group. b) Enhancing para-selectivity in substitution. c) Directly metallating an aromatic ring to achieve ortho-selectivity. d) Preventing polysubstitution in Friedel-Crafts alkylation.

28. Which of the following is an example of an activating ortho, para-directing group? a) −CN b) −SO3​H c) −F d) −CHO

29. Which of the following intermediates is formed in the Friedel-Crafts acylation but not in the Friedel-Crafts alkylation? a) Carbocation b) Acylium ion c) Arenium ion d) Alkyl radical

30. The conversion of an aryl ketone (from Friedel-Crafts acylation) to an alkylbenzene is an example of what kind of reaction? a) Oxidation b) Elimination c) Reduction d) Rearrangement

31. When nitrating fluorobenzene, why is the para product predominantly formed despite the inductive electron-withdrawal of fluorine? a) Steric hindrance at the ortho positions. b) Better orbital overlap at the para position. c) The inductive effect is weaker at the para position. d) The resonance effect of fluorine favors the para position.

32. Which of the following reagents is NOT typically used for Friedel-Crafts reactions? a) AlCl3​ b) FeBr3​ c) HCl d) BF3​

33. What is the outcome if benzene is treated with bromine without a Lewis acid catalyst? a) Bromobenzene is formed rapidly. b) No reaction occurs. c) Addition products are formed. d) A mixture of substitution and addition products.

34. The reaction of toluene with bromine (plus Lewis acid) yields predominantly which products? a) Meta-bromotoluene b) Ortho and para-bromotoluene c) Only para-bromotoluene d) Only ortho-bromotoluene

35. What is the approximate pKa of protonated acetone? a) 15 b) 7 c) -7 d) -15

36. Why are electron-withdrawing groups said to “deactivate” the benzene ring? a) They increase the basicity of the ring. b) They increase the electron density of the ring. c) They decrease the electron density of the ring, making it less nucleophilic. d) They cause the ring to become non-aromatic.

37. If a carboxylic acid is directly attached to a benzene ring (ArCOOH), what is its directing effect? a) Ortho, para-directing and activating. b) Meta-directing and activating. c) Ortho, para-directing and deactivating. d) Meta-directing and deactivating.

38. What is the term for molecules with the same kinds and numbers of atoms joined up in different ways? a) Isomers b) Isotopes c) Allotropes d) Polymers

39. In the context of electrophilic aromatic substitution, what is the ‘σ-complex’? a) The final product of the reaction. b) A non-aromatic carbocation intermediate. c) The catalyst used in the reaction. d) A stable resonance structure of benzene.

40. Which of the following statements about sulfonation is true? a) It is irreversible under all conditions. b) It can be reversed at high temperatures. c) It always gives ortho products. d) It requires a strong base.

Answer Key:

1. c) It is highly stable due to the aromaticity of its benzene ring.
2. c) 1.39A˚
3. b) Because addition reactions would disrupt its aromaticity.
4. b) Attack by the electrophile to form the cationic intermediate.
5. c) Arenium ion (σ-complex)
6. c) NO2+​
7. c) Concentrated HNO3​ and H2​SO4​
8. b) To generate the SO3​ electrophile.
9. c) It often leads to multiple substitutions and carbocation rearrangements.
10. d) Both primary and secondary
11. c) Acylium ion (RCO+)
12. c) Acylation introduces a deactivating group, preventing polysubstitution, and the product can be reduced to an alkylbenzene.
13. d) −OH
14. c) Their resonance electron-donating effect via a lone pair.
15. b) Acetanilide (amide derivative)
16. c) By hyperconjugation (σ-conjugation) and inductive effect.
17. b) Ortho and para
18. c) −CHO (aldehyde)
19. b) It withdraws electrons by resonance, primarily from the ortho and para positions.
20. d) Deactivating and ortho, para-directing.
21. b) Their strong inductive electron-withdrawing effect.
22. d) Fluorine
23. b) The more activating group.
24. c) Reduction
25. b) It changes a meta-directing group into an ortho, para-directing group.
26. c) To replace amino groups with various other substituents.
27. c) Directly metallating an aromatic ring to achieve ortho-selectivity.
28. c) −F
29. b) Acylium ion
30. c) Reduction
31. d) The resonance effect of fluorine favors the para position. (While steric hindrance plays a role, the text explicitly mentions the resonance effect as the reason for ortho/para directing, and that fluorine’s good overlap aids this.)
32. c) HCl
33. b) No reaction occurs.
34. b) Ortho and para-bromotoluene
35. c) -7
36. c) They decrease the electron density of the ring, making it less nucleophilic.
37. d) Meta-directing and deactivating. (Carboxylic acid groups are strongly electron-withdrawing by resonance and inductive effects.)
38. a) Isomers
39. b) A non-aromatic carbocation intermediate.
40. b) It can be reversed at high temperatures.