Chapter 12 Electrophilic and Nucleophilic Aromatic Substitution

Chapter 12 Electrophilic and Nucleophilic Aromatic Substitution

CHAPTER 12 Electrophilic and Nucleophilic Aromatic Substitution Aromatic compounds may undergo substitution reactions. Electrophilic aromatic substitutions (S E Ar, or sometimes EAS) are the central focus and these reactions are treated in the first 18 sections. Nucleophilic aromatic substitutions (S N Ar, or sometimes NAS) are treated in the last 3 sections. S E Ar reactions involve the substitution of a hydrogen atom on an aromatic ring. The reactions are initiated by a very reactive electronphile. The S E Ar mechanism is discussed in detail and can be used to explain regiochemistry of the reaction on substituted aromatic systems. S N Ar reactions differ from S E Ar in that these reactions involve the substitution of a leaving group. The S N Ar mechanism shares many similarities with S E Ar and, a familiarity with the S E Ar will help understanding the the S N Ar mechanism. These mechanisms involves a heavy does of resonance, so please review this topic from chapter 1. Chapter 12 Problems: 33, 34, 39, 40, 46, 49, 50, 53, 57, 59 Chapter 12-2

PREVIEW OF ELECTROPHILIC AND NUCLEOPHILIC AROMATIC SUBSTITUTIONS S E Ar is mechanistically related to previously presented electrophilic addition (chapter 6). Likewise, S N Ar is related to nucleophilic (aliphatic) substitution (chapters 4 and 8). Chapter 12-3

FIVE S E Ar REACTIONS 1. Nitration 2. Sulfonation 3. Halogenation 4. Friedel-Crafts Alkylation 5. Friedel-Crafts Acylation Chapter 12-4

GENERAL MECHANISM FOR S E Ar Two-step mechanism that begins with an electrophile removing electrons from an aromatic π bond, followed by a base removing a hydrogen to reform the alkene (aromaticity). Chapter 12-5

NITRATION OF BENZENE Overall reaction replaces a aromatic hydrogen with a nitro group (-NO 2 ) Requires the formation of the nitronium ion (NO 2+ ), a very good electrophile. Chapter 12-6

SULFONATION OF BENZENE Overall reaction replaces a aromatic hydrogen with a sulfonic acid group (-SO 3 H). Sulfur trioxide is suspected to be the reacting electrophile (SO 3 ). Chapter 12-7

HALOGENATION OF BENZENE Overall reaction replaces a aromatic hydrogen with a halide (-X), X = Br, Cl, I. Dihalogens are not electrophilic enough to react on their own, so an reactive species with an electron deficient halogen must be created. Chapter 12-8

FRIEDEL-CRAFTS ALKYLATION OF BENZENE Overall reaction replaces a aromatic hydrogen an alkyl group (-R). The reactive electrophile is a carbocation generated from an alkyl halide and a strong Lewis acid. Chapter 12-9

FRIEDEL-CRAFTS ALKYLATION OF BENZENE (cont.) Because the reactive electrophile is a carbocation, reactions will only work with 3 and 2 cations. Possible carbocation rearrangements may occur. Chapter 12-10

FRIEDEL-CRAFTS ACYLATION OF BENZENE Overall reaction replaces a aromatic hydrogen an acyl group (-COR). The reactive electrophile is an acylium ion which is generated with an acid halide and a strong Lewis acid. Chapter 12-11

REDUCTION OF ARYL KETONES TO METHYLENES Reduction of an aromatic acyl group leads to a (-CH 2 -); equivalent to an alkylation with a 1 carbocation. Chapter 12-12

REDUCTION OF ARYL KETONES TO METHYLENES Clemmensen reduction under acidic conditions. Wolff-Kishner reduction under basic condition. Chapter 12-13

REACTION RATES OF S E Ar Activating groups will increase S E Ar rates. Deactivating groups will decrease S E Ar rates. Chapter 12-14

REGIOSELECTIVITY IN S E Ar: EXAMPLE TOLUENE A methyl group directs the reaction to the ortho and para positions. ortho nitration meta nitration para nitration Chapter 12-15

REGIOSELECTIVITY IN S E Ar: EXAMPLE (TRIFLUOROMETYL)BENZENE A trifluoro-methyl group directs the reaction to the meta positions. ortho nitration meta nitration para nitration Chapter 12-16

REGIOSELECTIVITY IN S E Ar: EXAMPLE (TRIFLUOROMETYL)BENZENE Hammond s postulate is invoked to explain regiochemistry. Chapter 12-17

CLASSIFICATION OF SUBSTITUENTS Chapter 12-18

SUBSTITUENT EFFECT: ACTIVATING GROUPS Activating groups (aka electron donating groups or EDG) increase the overall reaction rate and direct ortho/para. Chapter 12-19

SUBSTITUENT EFFECT: DEACTIVATING GROUPS Deactivating groups (aka electron withdrawing groups or EWG) decrease the overall reaction rate and direct meta. Chapter 12-20

SUBSTITUENT EFFECT: HALOGENS Halogens are exceptions. They are decrease the reaction rate, but direct otho/para. Chapter 12-21

MULTIPLE SUBSTITUENTS Case 1: groups can reinforce each other. Chapter 12-22

MULTIPLE SUBSTITUENTS Case 2: sterics may also direct substitution. Also, groups work against each other; stronger activator wins. Chapter 12-23

RETROSYNTHETIC ANALYSIS For multiple substituted benzenes, be sure to order the reactions correctly. Chapter 12-24

RETROSYNTHETIC ANALYSIS Don t forget about Friedel-Crafts acylation combined with reductions. Chapter 12-25

S E Ar ON OTHER ARENES Regiochemistry determined by electrophilic addition generates the more stable σ- complexes. For naphthalene, resonance forms with aromaticity will increase stability over resonance forms without aromaticity. Chapter 12-26

S E Ar ON HETEROCYCLIC AROMATIC COMPOUNDS Regiochemistry determined by electrophilic addition generates the more stable σ- complexes. Chapter 12-27

NUCLEOPHILIC AROMATIC SUBSTITUTION: S N Ar Aryl halides can undergo nucleophilic substitution. Nitro groups ( NO 2 ) at the ortho or para positions to the halide ACTIVATE the reaction (unlike S E Ar reactions). Chapter 12-28

S N Ar MECHANISM: ADDITION-ELIMINATION Nucleophilic addition to the aryl ring produces a cyclohexadienyl anion. Nitro groups next to a carbanion have an additional resonance form. Dissociation of the leaving group regenerates aromaticity in the ring. Chapter 12-29

OTHER EXAMPLES OF S N Ar Hexafluorobenzene is susceptible to S N Ar. Heterocyclic compound with specifically placed electronegative atoms can also help stabilize anionic intermediates. Chapter 12-30

S N Ar MECHANISM: BENZYNE INTERMEDIATES* Halobenzene under stongly basic conditions can eliminate to produce a cyclic alkyne, called a benzyne. Nucleophilic attack of benzyne, followed by protonation of the carbanion completes the substitution product. * In Descriptive Passage section at the end of chapter 12 on pp. 507-9. Chapter 12-31