Chapter: Conjugate Addition and Nucleophilic Aromatic Substitution

1. Introduction to Addition-Elimination Reactions

Organic chemistry features a diverse array of reaction types. Among these, reactions that involve an initial addition step followed by an elimination, or vice-versa, are common. This chapter focuses on two significant classes of such reactions: conjugate addition (which is an addition reaction to an unsaturated system) and nucleophilic aromatic substitution (which involves an addition-elimination sequence on an aromatic ring).

2. Conjugate Addition (1,4-Addition to α,β-Unsaturated Carbonyls)

• Definition: Conjugate addition is a type of nucleophilic addition reaction where a nucleophile attacks the β-carbon of an α,β-unsaturated carbonyl compound (or similar unsaturated system), followed by subsequent protonation (often at the α-carbon or oxygen). This is also commonly referred to as 1,4-addition because the nucleophile adds to position 1 and the proton to position 4 of the conjugated system. When the nucleophile is a resonance-stabilized carbanion (like an enolate of a β-dicarbonyl compound), the reaction is specifically called a Michael addition.
• Substrates: The common substrates for conjugate addition are compounds containing a carbon-carbon double bond conjugated to a carbonyl group (or other electron-withdrawing groups like nitrile, nitro, or sulfone). Examples include:
  • α,β-unsaturated aldehydes (RCH=CH-CHO)
  • α,β-unsaturated ketones (RCH=CH-COR’)
  • α,β-unsaturated esters (RCH=CH-COOR’)
  • α,β-unsaturated nitriles (RCH=CH-CN)
• Nucleophiles: “Hard” vs. “Soft” Nucleophiles: The choice of nucleophile is critical in determining whether 1,2-addition (direct addition to the carbonyl) or 1,4-addition (conjugate addition) predominates.
  • “Hard” Nucleophiles (favors 1,2-addition): These are small, highly reactive, and non-polarizable nucleophiles with concentrated negative charge. They tend to attack the more electrophilic carbonyl carbon (charge control).
    • Examples: Grignard reagents (RMgX), organolithium reagents (RLi), hydride reducing agents (LiAlH4​, NaBH4​).
  • “Soft” Nucleophiles (favors 1,4-addition): These are larger, more polarizable, and less reactive nucleophiles with diffuse negative charge. They tend to attack the more electrophilic β-carbon (orbital control, favoring interaction with the LUMO of the conjugated system).
    • Examples: Organocuprates (Gilman reagents, R2​CuLi), thiols (RS−), amines (RNH2​, R2​NH), stabilized enolates (from β-dicarbonyls, malonic esters, acetoacetic esters), cyanide (CN−).
• Mechanism of Conjugate Addition:
  1. Nucleophilic Attack: The soft nucleophile attacks the β-carbon of the α,β-unsaturated carbonyl system. This causes the π electrons of the C=C bond to shift, and then the π electrons of the C=O bond to shift onto the oxygen atom, forming an enolate intermediate (specifically, a resonance-stabilized enolate).
  2. Protonation: The enolate intermediate is then protonated. This typically occurs at the α-carbon (either directly or via tautomerization from the enol formed by O-protonation), leading to the saturated carbonyl product.
• Regioselectivity (1,2- vs. 1,4-Addition):
  • Hard nucleophiles prefer 1,2-addition because they are highly reactive and react faster with the most positive center (the carbonyl carbon, which has a larger partial positive charge due to the inductive effect).
  • Soft nucleophiles prefer 1,4-addition because they react slower and are more selective. They prefer to react with the β-carbon, which is the site of the largest LUMO coefficient in the conjugated system (orbital control). The resulting enolate intermediate from 1,4-addition is also more stable due to resonance.
• Stereoselectivity: If new chiral centers are formed during conjugate addition, the reaction can be stereoselective, often forming a preferred diastereomer depending on steric and electronic factors during the nucleophilic attack and protonation steps.

3. Nucleophilic Aromatic Substitution (SN​Ar)

• Definition: Nucleophilic Aromatic Substitution (SN​Ar) is a class of substitution reactions where a nucleophile replaces a leaving group (usually a halogen) directly attached to an aromatic ring. This is fundamentally different from Electrophilic Aromatic Substitution (EAS), which is a common reaction of benzene.
• Conditions for SN​Ar (Addition-Elimination Mechanism): For a simple SN​Ar reaction to occur, specific conditions are generally required:
  1. Strong Electron-Withdrawing Groups (EWGs) on the Ring: There must be one or more strong electron-withdrawing groups (e.g., −NO2​, −CN, −CHO, −COR, −SO2​R) located ortho or para to the leaving group. These EWGs are crucial for stabilizing the negative charge that develops on the aromatic ring in the intermediate.
  2. Good Leaving Group: A good leaving group (such as a halogen, typically F > Cl > Br > I, with Fluorine often being the best due to its electronegativity and ability to stabilize negative charge in the transition state leading to the intermediate) must be present on the aromatic ring.
  3. Strong Nucleophile: A strong nucleophile is necessary to initiate the reaction by attacking the relatively unreactive aromatic ring.
• Mechanism (Addition-Elimination Mechanism): SN​Ar typically proceeds via a two-step addition-elimination pathway:
  1. Nucleophilic Attack (Rate-Determining Step): The strong nucleophile attacks the carbon atom bearing the leaving group. This step disrupts the aromaticity temporarily, forming a resonance-stabilized anionic intermediate known as a Meisenheimer complex (or σ-complex). The negative charge in this intermediate is delocalized onto the ortho and para positions (relative to the attacking nucleophile and leaving group). The presence of strong EWGs at these ortho or para positions is essential because they can accept and further delocalize this negative charge, thereby stabilizing the Meisenheimer complex and lowering the activation energy for this rate-determining step.
  2. Leaving Group Departure (Fast Step): The leaving group departs from the Meisenheimer complex, taking its bonding electrons with it. This step restores the aromaticity of the ring, which is a highly favorable process, making this step fast.
• Regioselectivity: Nucleophilic attack (and thus substitution) preferentially occurs at positions ortho or para to the strong electron-withdrawing groups. This is because these are the only positions where the negative charge developed in the Meisenheimer complex can be directly delocalized onto the electron-withdrawing group via resonance, leading to greater stabilization of the intermediate. Substitution meta to an EWG is much less favored.
• Stereochemistry: For SN​Ar reactions, if the carbon undergoing substitution is a chiral center (which is rare in simple aryl halides but possible in more complex systems), racemization can occur if the Meisenheimer complex adopts a planar configuration. However, typically, the stereochemical implications at the substitution site are not a primary consideration as the aromatic carbons are usually achiral.
• Comparisons to Electrophilic Aromatic Substitution (EAS):
  • EAS: Electrophilic attack (electron-deficient species attacks the electron-rich aromatic ring). Favored by activating (electron-donating) groups. Forms a positively charged intermediate.
  • SN​Ar: Nucleophilic attack (electron-rich species attacks the electron-deficient carbon on the ring). Favored by deactivating (electron-withdrawing) groups at ortho and para positions. Forms a negatively charged intermediate.

4. Other Types of Nucleophilic Aromatic Substitution

• Elimination-Addition Mechanism (Benzyne Mechanism):
  • This mechanism operates when aryl halides lack strong ortho or para electron-withdrawing groups. It typically requires very harsh conditions, such as extremely strong bases (e.g., sodium amide, NaNH2​) and often high temperatures.
  • Mechanism:
    1. Elimination: The strong base abstracts an ortho-hydrogen to the halogen, simultaneously forcing the leaving group to depart. This concerted elimination forms a highly strained and reactive intermediate called benzyne, which features a highly unstable triple bond within the benzene ring (an additional π bond that is perpendicular to the existing aromatic π system).
    2. Addition: A nucleophile rapidly adds across the triple bond of the benzyne intermediate.
  • Regioselectivity: The benzyne intermediate is often symmetrical, but if substituents make it unsymmetrical, the nucleophile can add to either end of the triple bond, leading to a mixture of products. This has been confirmed by isotope labeling experiments.
  • Evidence: The benzyne intermediate has been trapped and observed spectroscopically.
• Oxidative Addition/Reductive Elimination (Transition Metal Catalysis):
  • While not strictly “addition-elimination” or “elimination-addition” as described above, many important nucleophilic aromatic substitution-like reactions in modern synthesis proceed via transition metal catalysis (e.g., Palladium-catalyzed reactions like the Buchwald-Hartwig amination for forming C-N bonds on aromatic rings, or cross-coupling reactions for forming C-C bonds).
  • These mechanisms typically involve oxidative addition of the aryl halide to the metal, followed by transmetalation and reductive elimination. They are highly versatile but mechanistically distinct from the classical SN​Ar or benzyne pathways.

5. Summary and Key Differences

Feature	Conjugate Addition (1,4-addition)	SN​Ar (Addition-Elimination)	Benzyne Mechanism (Elimination-Addition)
Substrate	α,β-Unsaturated carbonyl compounds	Aryl halide with ortho/para EWGs	Aryl halide without ortho/para EWGs, with ortho-H
Reagents	Soft nucleophiles (e.g., organocuprates, amines, thiols, enolates)	Strong nucleophiles	Very strong bases (e.g., NaNH2​)
Mechanism Type	Addition (to alkene)	Addition-Elimination (Meisenheimer complex)	Elimination-Addition (Benzyne intermediate)
Intermediate	Enolate (then protonated)	Meisenheimer complex (anionic σ-complex)	Benzyne
Role of EWGs	Not directly involved	Crucial for stabilizing Meisenheimer intermediate (must be ortho/para)	Not required; if present, mechanism usually switches to SN​Ar
Leaving Group	No leaving group in the sense of substitution	Halogen, etc., departs after nucleophilic attack	Halogen departs before nucleophilic attack (via E2-like step)
Regioselectivity	β-carbon attack (1,4-addition)	Ortho/para to EWG	Can be a mixture if benzyne is unsymmetrical
Stereochemistry	Can be stereoselective if new chiral center is formed	Usually no primary stereochemical implications at aromatic carbon	Can lead to mixtures if benzyne is unsymmetrical

Multiple Choice Questions (MCQ) on Conjugate Addition and Nucleophilic Aromatic Substitution

Instructions: Choose the best answer for each question.

1. What is another common name for 1,4-addition to an α,β-unsaturated carbonyl compound? a) Direct addition b) Electrophilic addition c) Conjugate addition d) Hydration

2. Which carbon atom of an α,β-unsaturated carbonyl compound is attacked by a nucleophile in a 1,4-addition? a) The carbonyl carbon b) The α-carbon c) The β-carbon d) The carbon γ to the carbonyl

3. Which of the following is considered a “soft” nucleophile and typically favors conjugate addition? a) Grignard reagent (RMgX) b) Organolithium reagent (RLi) c) Organocuprate (Gilman reagent, R2​CuLi) d) Hydride (LiAlH4​)

4. What type of intermediate is formed immediately after nucleophilic attack in a conjugate addition reaction? a) A carbocation b) A radical c) An enolate d) A Meisenheimer complex

5. “Hard” nucleophiles generally favor which type of addition to α,β-unsaturated carbonyls? a) 1,2-addition b) 1,4-addition c) Elimination d) Substitution

6. Which of the following is an example of a nucleophile that typically favors 1,2-addition over 1,4-addition? a) Amine (RNH2​) b) Thiol (RSH) c) Grignard reagent (CH3​MgBr) d) Stabilized enolate

7. What is the overall definition of Nucleophilic Aromatic Substitution (SN​Ar)? a) An electrophile replacing a group on an aromatic ring. b) A nucleophile replacing a group on an aromatic ring. c) A radical replacing a group on an aromatic ring. d) Addition of a nucleophile across an aromatic double bond.

8. For SN​Ar (addition-elimination mechanism) to occur efficiently, what kind of groups must be present on the aromatic ring, located ortho or para to the leaving group? a) Electron-donating groups (EDGs) b) Sterically hindered groups c) Electron-withdrawing groups (EWGs) d) Alkyl groups

9. What is the rate-determining intermediate formed during the SN​Ar (addition-elimination) mechanism? a) Carbocation b) Radical c) Benzyne d) Meisenheimer complex (σ-complex)

10. In SN​Ar reactions, what is generally the best leaving group among halogens? a) I b) Br c) Cl d) F

11. Why are electron-withdrawing groups crucial for SN​Ar (addition-elimination)? a) They make the aromatic ring more nucleophilic. b) They stabilize the positive charge of the intermediate. c) They stabilize the negative charge of the Meisenheimer complex by resonance. d) They act as the leaving group.

12. Nucleophilic Aromatic Substitution (SNAr) is typically favored by which type of groups on the aromatic ring? a) Activating groups b) Deactivating groups (electron-withdrawing) c) Ortho, para-directing groups d) Meta-directing groups (generally)

13. In the Meisenheimer complex, the negative charge is delocalized primarily onto which positions relative to the attacking nucleophile? a) Meta only b) Ortho and meta c) Ortho and para d) Para only

14. What is the typical stereochemical outcome if a new chiral center is formed during an SN​Ar reaction? a) Complete inversion b) Complete retention c) Racemization (due to planar intermediate) d) It is strictly stereospecific.

15. Which of the following conditions would lead to a mixture of products in Nucleophilic Aromatic Substitution via the benzyne mechanism? a) A symmetrical benzyne intermediate. b) A strong EWG ortho to the leaving group. c) An unsymmetrical benzyne intermediate. d) A weak nucleophile.

16. What is the key intermediate in the Elimination-Addition mechanism of nucleophilic aromatic substitution? a) Carbocation b) Radical c) Benzyne d) Meisenheimer complex

17. What kind of base is typically required for the benzyne mechanism of nucleophilic aromatic substitution? a) Weak base (e.g., H2​O) b) Strong nucleophile (e.g., CN−) c) Very strong base (e.g., NaNH2​) d) Lewis acid

18. Which regioselectivity is characteristic of SN​Ar (addition-elimination)? a) Markovnikov addition b) Anti-Markovnikov addition c) Substitution ortho or para to EWGs d) Substitution meta to EWGs

19. What is the purpose of isotope labeling studies in understanding the benzyne mechanism? a) To determine reaction rate. b) To identify the position of substituents. c) To confirm the symmetrical nature of the benzyne intermediate. d) To measure the equilibrium constant.

20. Which of these is a typical substrate for conjugate addition reactions? a) Alkene b) Alkane c) α,β-unsaturated ketone d) Aromatic ring

21. A reaction that involves an initial addition step followed by an elimination step is characteristic of which mechanism? a) E1 b) E2 c) SN​Ar (addition-elimination) d) Benzyne mechanism

22. Which nucleophile would likely prefer 1,2-addition to propenal (CH2​=CH-CHO)? a) CH3​Li b) (CH3​)2​CuLi c) CH3​NH2​ d) CH3​SH

23. Which statement about the Meisenheimer complex is true? a) It is a positively charged intermediate. b) It is formed in the fast step of SN​Ar. c) It is resonance-stabilized. d) It is formed from the elimination-addition mechanism.

24. Why is direct nucleophilic substitution on an unsubstituted benzene ring typically not observed? a) Benzene is electron-rich and repels nucleophiles. b) It would lead to an unstable carbocation. c) It would disrupt aromaticity and form an unstable anion. d) It only reacts with electrophiles.

25. If a benzene ring has a nitro group and a chloro group at para positions, and it reacts with a strong nucleophile, where would the substitution most likely occur? a) At the carbon bearing the nitro group. b) At the carbon bearing the chloro group. c) At a meta carbon to both groups. d) No reaction would occur.

26. Which type of solvent would typically favor an SN​Ar reaction? a) Non-polar solvent b) Protic solvent c) Aprotic solvent d) Both protic and aprotic can work, but polar helps.

27. What is the main difference in the role of a leaving group in SN​Ar (addition-elimination) versus the benzyne mechanism? a) In SN​Ar, it leaves before nucleophilic attack; in benzyne, it leaves after. b) In SN​Ar, it leaves after nucleophilic attack; in benzyne, it leaves before. c) It is not involved in SN​Ar but is crucial for benzyne. d) Its role is identical in both mechanisms.

28. Which reaction is known to form new C-N or C-O bonds on aromatic rings using transition metal catalysis, mechanistically distinct from classic SN​Ar? a) Friedel-Crafts reaction b) Suzuki coupling c) Buchwald-Hartwig amination d) Diels-Alder reaction

29. The term “Michael addition” refers to a specific type of conjugate addition where the nucleophile is: a) A Grignard reagent. b) An organocuprate. c) A stabilized enolate. d) An amine.

30. Which of the following is an example of an α,β-unsaturated carbonyl compound? a) Acetone (CH3​COCH3​) b) Acrolein (CH2​=CH-CHO) c) Ethanol (CH3​CH2​OH) d) Benzene (C6​H6​)

31. The driving force for the elimination step in the benzyne mechanism (forming benzyne) is: a) Formation of a stable carbocation. b) Resonance stabilization of a radical. c) The strong basicity of the attacking nucleophile. d) The stability gained by forming a triple bond.

32. In an α,β-unsaturated ketone, the carbonyl carbon is often referred to as the 1-position. What is the β-carbon often referred to as? a) 2-position b) 3-position c) 4-position d) 5-position

33. What kind of nucleophile is typically required for a Michael addition? a) A hard nucleophile. b) A soft, stabilized enolate (or similar carbanion). c) A strong acid. d) A radical.

34. What effect would adding a strong electron-donating group (EDG) at the ortho or para position have on the rate of an SN​Ar reaction? a) Increase the rate. b) Decrease the rate. c) Have no effect. d) Change the mechanism to EAS.

35. If an aromatic ring has a leaving group and a strong EWG at the meta position, what would be the expected reactivity towards SN​Ar (addition-elimination)? a) Very high reactivity. b) Moderate reactivity. c) Very low reactivity. d) Reaction would proceed via benzyne.

36. The major product of a 1,4-addition to cyclohexenone with R2​CuLi would be: a) An alcohol by 1,2-addition. b) A saturated ketone with R added to the β-carbon. c) A rearrangement product. d) An elimination product.

37. Which of the following conditions would favor the benzyne mechanism over the addition-elimination SN​Ar mechanism? a) Presence of ortho NO2​ groups. b) Using LiAlH4​ as nucleophile. c) Absence of ortho/para EWGs on the aryl halide and use of a very strong base. d) Using NaF as the nucleophile.

38. Which of these is a similarity between conjugate addition and SN​Ar? a) Both involve carbocation intermediates. b) Both are favored by strong electron-donating groups. c) Both involve nucleophilic attack on an unsaturated carbon system. d) Both require an anti-periplanar transition state.

39. The leaving group in the benzyne mechanism leaves before the nucleophile attacks. This implies it’s an analogy to which elimination mechanism? a) E1 b) E2 c) E1cb d) E3

40. In α,β-unsaturated esters, what is the relative electrophilicity of the carbonyl carbon vs. the β-carbon? a) Carbonyl carbon is always more electrophilic. b) β-carbon is always more electrophilic. c) Both are electrophilic; the nucleophile’s “hardness” determines the site of attack. d) Neither is electrophilic.

Answer Key with Explanations

1. c) Conjugate addition.
   • Explanation: 1,4-addition to α,β-unsaturated carbonyls is commonly known as conjugate addition because the nucleophile adds to the end of the conjugated system.
2. c) The β-carbon.
   • Explanation: In 1,4-addition (conjugate addition), the nucleophile attacks the β-carbon, which is two carbons away from the carbonyl carbon in the conjugated system.
3. c) Organocuprate (Gilman reagent, R2​CuLi).
   • Explanation: Organocuprates are classic “soft” nucleophiles that show a strong preference for conjugate (1,4) addition due to orbital control. Grignard and organolithium reagents are “hard” and prefer 1,2-addition.
4. c) An enolate.
   • Explanation: Nucleophilic attack on the β-carbon of an α,β-unsaturated carbonyl pushes electrons, ultimately forming a resonance-stabilized enolate intermediate.
5. a) 1,2-addition.
   • Explanation: “Hard” nucleophiles are highly reactive and tend to attack the most positive center (the carbonyl carbon), leading to direct 1,2-addition.
6. c) Grignard reagent (CH3​MgBr).
   • Explanation: Grignard reagents are “hard” nucleophiles that preferentially attack the carbonyl carbon (1,2-addition). Amines, thiols, and stabilized enolates are “soft” nucleophiles.
7. b) A nucleophile replacing a group on an aromatic ring.
   • Explanation: Nucleophilic Aromatic Substitution involves a nucleophile replacing a leaving group directly attached to an aromatic ring, distinguishing it from electrophilic substitution.
8. c) Electron-withdrawing groups (EWGs).
   • Explanation: Strong electron-withdrawing groups (like nitro, cyano, carbonyl) at ortho or para positions are essential in SN​Ar to stabilize the developing negative charge in the Meisenheimer complex intermediate.
9. d) Meisenheimer complex (σ-complex).
   • Explanation: The Meisenheimer complex is the resonance-stabilized anionic intermediate formed in the rate-determining step of the SN​Ar (addition-elimination) mechanism.
10. d) F.
    • Explanation: In SN​Ar (addition-elimination), fluorine is often the best leaving group among halogens, despite being a poor leaving group in SN​1/SN​2. This is because its high electronegativity helps stabilize the negative charge in the transition state leading to the Meisenheimer complex.
11. c) They stabilize the negative charge of the Meisenheimer complex by resonance.
    • Explanation: The EWGs located ortho or para to the leaving group can delocalize the negative charge that develops on the ring in the Meisenheimer complex, thus lowering the activation energy for the rate-determining step.
12. b) Deactivating groups (electron-withdrawing).
    • Explanation: Unlike EAS, which is favored by activating groups, SN​Ar is favored by strong deactivating (electron-withdrawing) groups.
13. c) Ortho and para.
    • Explanation: The negative charge in the Meisenheimer complex is delocalized through resonance to the ortho and para positions (relative to the carbon undergoing substitution).
14. c) Racemization (due to planar intermediate).
    • Explanation: If the carbon undergoing substitution becomes a chiral center after reaction, the planar nature of the Meisenheimer complex allows attack from either face, typically leading to a racemic mixture.
15. c) An unsymmetrical benzyne intermediate.
    • Explanation: If the benzyne intermediate is unsymmetrical (due to other substituents on the ring), the incoming nucleophile can add to either end of the triple bond, leading to a mixture of positional isomers.
16. c) Benzyne.
    • Explanation: The Elimination-Addition mechanism proceeds through a highly reactive benzyne intermediate, which contains a triple bond within the aromatic ring.
17. c) Very strong base (e.g., NaNH2​).
    • Explanation: The benzyne mechanism requires an extremely strong base (like sodium amide) to abstract an ortho-hydrogen and simultaneously induce the departure of the leaving group to form the benzyne.
18. c) Substitution ortho or para to EWGs.
    • Explanation: In SN​Ar (addition-elimination), nucleophilic attack is directed to the carbon bearing the leaving group, provided there are strong EWGs ortho or para to it.
19. c) To confirm the symmetrical nature of the benzyne intermediate.
    • Explanation: Isotope labeling studies (e.g., using \text{^{14}C} or deuterium) have shown that the incoming nucleophile can attach to either of the two carbons involved in the benzyne triple bond, confirming its symmetrical (or near-symmetrical if substituted) nature.
20. c) α,β-unsaturated ketone.
    • Explanation: α,β-unsaturated carbonyl compounds (like ketones, aldehydes, esters) are the classic substrates for conjugate addition reactions.
21. c) SN​Ar (addition-elimination).
    • Explanation: The SN​Ar mechanism is a classic example of an addition-elimination sequence, where the nucleophile first adds to the ring, and then the leaving group is eliminated.
22. a) CH3​Li.
    • Explanation: CH3​Li (methyllithium) is an organolithium reagent, a “hard” nucleophile that would preferentially attack the carbonyl carbon (1,2-addition) of propenal.
23. c) It is resonance-stabilized.
    • Explanation: The Meisenheimer complex is an anionic intermediate whose negative charge is extensively delocalized by resonance within the aromatic ring and onto any ortho or para EWGs, contributing to its stability.
24. a) Benzene is electron-rich and repels nucleophiles.
    • Explanation: Unsubstituted benzene is highly electron-rich. Nucleophiles (also electron-rich) are repelled by the benzene ring, making direct nucleophilic attack unfavorable and requiring strong EWGs to make the ring electrophilic enough for SN​Ar.
25. b) At the carbon bearing the chloro group.
    • Explanation: In SN​Ar, the nucleophile replaces the leaving group. Here, the chloro group is the leaving group, and the nitro group is an activating EWG para to it, facilitating the substitution at the carbon bearing the chloro group.
26. d) Both protic and aprotic can work, but polar helps.
    • Explanation: While polar solvents (both protic and aprotic) are generally good for dissolving ionic reactants and stabilizing charged intermediates/transition states, SN​Ar doesn’t have as strong a preference as SN​1 or SN​2 for protic vs. aprotic. Polar solvents are beneficial overall due to their ability to stabilize charge, aiding the formation of the anionic Meisenheimer complex.
27. b) In SN​Ar, it leaves after nucleophilic attack; in benzyne, it leaves before.
    • Explanation: This is a key mechanistic difference. In SN​Ar, the nucleophile adds first, forming the Meisenheimer complex, then the leaving group departs. In the benzyne mechanism, the leaving group and an ortho-hydrogen are eliminated first, forming benzyne, before the nucleophile adds.
28. c) Buchwald-Hartwig amination.
    • Explanation: The Buchwald-Hartwig amination is a major example of a Palladium-catalyzed reaction that forms new C-N bonds on aromatic rings, representing a modern approach to nucleophilic aromatic substitution that involves transition metal catalysis, distinct from the classical SN​Ar or benzyne mechanisms.
29. c) A stabilized enolate.
    • Explanation: Michael addition is a specific type of conjugate addition where the nucleophile is a stabilized carbanion, typically an enolate derived from a β-dicarbonyl compound.
30. b) Acrolein (CH2​=CH-CHO).
    • Explanation: Acrolein is an α,β-unsaturated aldehyde, containing a carbon-carbon double bond conjugated to a carbonyl group.
31. c) The strong basicity of the attacking nucleophile.
    • Explanation: The primary driving force for the elimination step (which forms the benzyne) is the abstraction of an ortho-hydrogen by an extremely strong base, simultaneously forcing the leaving group to depart.
32. c) 4-position.
    • Explanation: In 1,4-addition, the nucleophile adds to the β-carbon (position 4) relative to the carbonyl oxygen (position 1).
33. b) A soft, stabilized enolate (or similar carbanion).
    • Explanation: Michael additions specifically utilize soft, stabilized carbanions (like enolates from active methylene compounds) as nucleophiles to perform conjugate addition.
34. b) Decrease the rate.
    • Explanation: Electron-donating groups (EDGs) would destabilize the negatively charged Meisenheimer complex intermediate, thereby increasing the activation energy and decreasing the rate of an SN​Ar reaction.
35. c) Very low reactivity.
    • Explanation: For the addition-elimination SN​Ar mechanism, strong EWGs must be ortho or para to the leaving group to stabilize the Meisenheimer complex. An EWG at the meta position cannot directly delocalize the negative charge, leading to very low reactivity.
36. b) A saturated ketone with R added to the β-carbon.
    • Explanation: R2​CuLi is a soft nucleophile, so it will undergo 1,4-conjugate addition to cyclohexenone. The result, after protonation, is a saturated ketone with the R group added to the β-carbon.
37. c) Absence of ortho/para EWGs on the aryl halide and use of a very strong base.
    • Explanation: The benzyne mechanism is favored when the classical SN​Ar pathway is disfavored (i.e., no ortho/para EWGs) and an extremely strong base is present to enable the initial elimination step.
38. c) Both involve nucleophilic attack on an unsaturated carbon system.
    • Explanation: Conjugate addition involves nucleophilic attack on the β-carbon of an α,β-unsaturated system. SN​Ar involves nucleophilic attack on an electrophilic carbon of an aromatic (unsaturated) ring. Both are nucleophilic processes.
39. b) E2.
    • Explanation: The benzyne mechanism’s first step, the elimination of HX to form the triple bond, is a concerted process involving an ortho-hydrogen and the halogen, analogous to an E2 elimination reaction.
40. c) Both are electrophilic; the nucleophile’s “hardness” determines the site of attack.
    • Explanation: In α,β-unsaturated systems, both the carbonyl carbon and the β-carbon are electrophilic. The regioselectivity (1,2- vs. 1,4-addition) is primarily governed by the “hardness” or “softness” of the attacking nucleophile.