OC 2/e Ch 20 - Cengage

OC 2/e Ch 20 - Cengage

21 Organic Chemistry William H. Brown & Christopher S. Foote 21-1 21 Aromatics II Chapter 21 Chapter 20 21-2 21 Reactions of Benzene The most characteristic reaction of aromatic compounds is substitution at a ring carbon Halogenation: H + Cl2 FeCl3

Cl + HCl Chlorobenzene Nitration: H + HNO3 H2 SO4 NO2 + H2 O Nitrobenzene 21-3 21 Reactions of Benzene Sulfonation: H + SO3 H2 SO4 SO3 H Benzenesulfonic acid Alkylation: H + RX AlX3

R + HX An alkylbenzene Acylation: H O + RCX AlX3 O CR + HX An acylbenzene 21-4 21 Electrophilic Aromatic Sub Electrophilic aromatic substitution: a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile H +

+ E E + + H We study several common types of electrophiles how each is generated the mechanism by which each replaces hydrogen 21-5 21 Chlorination Step 1: formation of a chloronium ion Cl Fe Cl + Cl Chlorine Ferric chloride (a Lewis base)(a Lewis acid)

Cl Cl Cl + Cl Cl Fe Cl + Cl FeCl4 Cl A molecular complex An ion pair containing a with a positive charge on chlorinechloronium ion 21-6 21 Chlorination Step 2: attack of the chloronium ion on the aromatic ring + Cl+

slow, rate determining + H + Cl H H Cl + Cl Resonance-stabilized cation intermediate; the pos charge is delocalized onto three atoms of the ri Step 3: proton transfer regenerates the aromatic character of the ring + H fast

+ Cl FeCl3 Cl Cation intermediate Cl + HCl + FeCl3 Chlorobenzene 21-7 21 EAS: General Mechanism A general mechanism + Step 1: H + E slow, rate determining Electrophile +

Step 2: H E fast + H E Resonance-stabilized cation intermediate E + H+ General question: what is the electrophile and how is it generated? 21-8 21 Nitration The electrophile is NO2+, generated in this way

: H O : NO2 + H O SO3 H H + H O : NO2 + HSO4 Nitric acid H + H O : NO2 H : + : H O : : + :O=N=O: Nitronium ion 21-9 21 Nitration Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile)

H + + NO2 NO2 + H NO2 H + NO2 + Resonance-stabilized cation intermedia Step 2: proton transfer regenerates the aromatic ring H H 2O +

NO2 + NO2 + H 3O+ Nitrobenzene 21-10 21 Nitration A particular value of nitration is that the nitro group can be reduced to a 1 amino group O2N COOH + 3H2 Ni (3 atm) 4-Nitrobenzoic acid H2N COOH + 2H2O

4-Aminobenzoic acid 21-11 21 Sulfonation Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide + SO3 Benzene H2 SO4 SO3 H Benzenesulfonic acid 21-12 21 Friedel-Crafts Alkylation Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group Cl +

Benzene AlCl3 + HCl 2-Chloropropane Cumene (Isopropyl chloride) (Isopropylbenzene) 21-13 21 Friedel-Crafts Alkylation Step 1: formation of an alkyl cation as an ion pair R Cl : Cl : : + Al-Cl Cl + : Cl : Al Cl

R Cl Cl + - R AlCl4 An ion pair containing a carbocation Step 2: attack of the alkyl cation on the aromatic ring + + + R H R + H

H R +R A resonance-stabilized cation Step 3: proton transfer regenerates the aromatic ring + H R + Cl AlCl3 R + AlCl3 + HCl 21-14 21 Friedel-Crafts Alkylation There are two major limitations on Friedel-Crafts alkylations 1. carbocation rearrangements are common +

Benzene Cl Isobutyl chloride AlCl3 + HCl tert-Butylbenzene 21-15 21 Friedel-Crafts Alkylation the isobutyl chloride/AlCl3 complex rearranges to the tert-butyl cation/AlCl4- ion pair, which is the electrophile CH3 CH3 CHCH2 -Cl + AlCl3 Isobutyl chloride CH3 + - CH3 C-CH2 -Cl-AlCl3

CH3 CH 3 C + AlCl 4 - CH3 H Isobutyl chloride-aluminum tert-Butyl cation/AlCl 4 chloride complex ion pair 21-16 21 Friedel-Crafts Alkylation 2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-withdrawing groups O CH O CR O COH O COR

SO3 H C N NO2 NR3 CF3 CCl3 O CNH2 + 21-17 21 Friedel-Crafts Acylation Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group O + CH3CCl

Benzene O AlCl3 Acetyl chloride Cl + HCl Acetophenone O O AlCl3 4-Phenylbutanoyl chloride + HCl -Tetrlon e 21-18 21 Friedel-Crafts Acylation

The electrophile is an acylium ion O Cl (1) R-C Cl + Al-Cl Cl An acyl Aluminum chloride chloride O O + Cl (2) R-C Cl Al Cl R-C + AlCl4 Cl A molecular complex An ion pair with a positive charge containing an charge on chlorine acylium ion 21-19

21 Friedel-Crafts Acylation an acylium ion is a resonance hybrid of two major contributing structures + R-C O :: complete valence shells + R-C O: The more important contributing structure F-C acylations are free of a major limitation of F-C alkylations; acylium ions do not rearrange 21-20 21 Friedel-Crafts Acylation A special value of F-C acylations is preparation of

unrearranged alkylbenzenes O + Cl AlCl3 2-Methylpropanoyl chloride O N2H4, KOH diethylene glycol Isobutylbenzene 2-Methyl-1- phenyl-1-propanone 21-21 21 Other Aromatic Alkylations Carbocations are generated by treatment of an alkene with a protic acid, most commonly H2SO4, H3PO4, or HF/BF3 + Benzene

CH3CH=CH2 Propene H3PO4 Cumene 21-22 21 Other Aromatic Alkylations by treating an alkene with a Lewis acid AlCl3 + Benzene Cyclohexene Phenylcyclohexane and by treating an alcohol with H2SO4 or H3PO4 + HO H3 PO4 + H2 O

Benzene 2-Methyl-2-propanol 2-Methyl-2(tert-Butyl alcohol) phenylpropane (tert-Butylbenzene 21-23 21 Di- and Polysubstitution Existing groups on a benzene ring influence further substitution in both orientation and rate Orientation: certain substituents direct preferentially to ortho & para positions; others direct preferentially to meta positions substituents are classified as either ortho-para directing or meta directing 21-24 21 Di- and Polysubstitution Rate certain substituents cause the rate of a second substitution to be greater than that for benzene itself;

others cause the rate to be lower substituents are classified as activating or deactivating toward further substitution 21-25 21 Di- and Polysubstitution -OCH3 is ortho-para directing OCH3 OCH3 Br + Br2 Anisole CH3 COOH OCH3 + o-Bromoanisole (4%) + HBr Br p-Bromo

anisole (96%) 21-26 21 Di- and Polysubstitution -NO2 is meta directing NO2 + HNO3 Nitrobenzene H2 SO4 100C NO2 NO2 NO2 + NO2 m-Dinitrobenzene (93%) o-Dinitrobenzene NO2

+ + H2 O NO2 p-Dinitrobenzene Less than 7% combined 21-27 21 Di- and Polysubstitution Strongly activating : NH2 O Moderately : activating NHCR Weakly activating : NHR :

NR2 : O NHCAr : O OCR : : OH : : OR : : O OCAr : R : Ortho-para Weakly Directing deactivating :F:

: Cl : : : Br : : : :I : O O O O CH CR COH COR Moderately deactivating O CNH2 SO3 H C N Strongly +

CF3 CCl3 Meta deactivating Directing NO2 NH3 21-28 21 Di- and Polysubstitution From the information in Table 21.1, we can make these generalizations alkyl, phenyl, and all other groups in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other groups are meta directing all ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating 21-29 21 Di- and Polysubstitution the order of steps is important CH3

COOH HNO3 K2 Cr2O7 H2SO4 H2SO4 CH3 K2 Cr2 O7 H2 SO4 NO2 NO2 p-Nitrobenzoic acid COOH COOH HNO3 H2SO4

NO2 m-Nitrobenzoic acid 21-30 21 Theory of Directing Effects The rate of EAS is limited by the slowest step in the reaction For almost every EAS, the rate-determining step is attack of E+ on the aromatic ring to give a resonance-stabilized cation intermediate The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction 21-31 21 Theory of Directing Effects

For ortho-para directors, ortho-para attack forms a more stable cation than meta attack ortho-para products are formed faster than meta products For meta directors, meta attack forms a more stable cation than ortho-para attack meta products are formed faster than ortho-para products 21-32 21 Theory of Directing Effects -OCH3; assume meta attack OCH3 + NO2 + OCH3 + H NO2 (a)

slow OCH3 + OCH3 fast H -H+ H NO2 (b) + NO2 OCH3 NO2 (c) 21-33 21 Theory of Directing Effects -OCH3: assume ortho-para attack OCH3

OCH3 + NO2 + slow : :OCH3 + : : :OCH3 : : OCH3 OCH3 + NO2 (d) fast

-H+ + H NO2 + H NO2 (e) H NO2 (f) H NO2 (g) 21-34 21 Theory of Directing Effects -NO2; assume meta attack

NO2 + NO2 + NO2 + H NO2 (a) slow NO2 + NO2 NO2 fast H -H+ H NO2 (b) + NO2

NO2 (c) 21-35 21 Theory of Directing Effects -NO2: assume ortho-para attack NO2 + NO2 + slow NO2 + H NO2 (d) NO2 NO2 + H NO2 (e) + H

NO2 fast -H+ NO2 (f) NO2 21-36 21 Activating-Deactivating Any resonance effect, effect such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS Any resonance or inductive effect, effect such as that of -NO2, -CN, -CO, or -SO3H, that decreases electron density on the ring deactivates the ring toward

further EAS 21-37 21 Activating-Deactivating Any inductive effect, effect such as that of -CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS Any inductive effect, effect such as that of -halogen, NR3+, -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS 21-38 21 Halogens for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger the net effect is that halogens are deactivating but ortho-para directing :

:Cl: + +E : :Cl : + H E + :Cl : H E 21-39 21 Nucleophilic Aromatic Sub.

Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways They do undergo nucleophilic substitutions, but by mechanisms quite different from those of nucleophilic aliphatic substitution Nucleophilic aromatic substitutions are far less common than electrophilic aromatic substitutions 21-40 21 Benzyne Intermediates When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide. Neutralization with HCl gives phenol. - Cl +

O Na + 2NaOH Chlorobenzene H2O pressure, 300oC + NaCl + H2O Sodium phenoxide 21-41 21 Benzyne Intermediates the same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol CH3 CH3 Cl 1. NaOH, heat, pressure 2. HCl, H2 O CH3 OH

+ OH 2-Methylphenol3-Methylphenol (o-Cresol) (m-Cresol) the same type of reaction can be brought about using of sodium amide in liquid ammonia CH3 CH3 + NaNH2 Cl NH3 (l) NaCl + o (-33C) CH3 + NH2 NH2

4-Methyl3-Methylaniline aniline (p-Toluidine) (m-Toluidine) 21-42 21 Benzyne Intermediates -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products CH3 CH3 NaNH2 Cl H -elim in tion A benzyne intermediate 21-43 21 Nu Addition-Elimination when an aryl halide contains electron-withdrawing NO 2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily

- Cl NO2 Na2 CO3, H2 O + O Na NO2 100oC NO2 1-Chloro-2,4dinitrobenzene NO2 Sodium 2,4-dinitrophenoxide neutralization with HCl gives the phenol 21-44 21 Meisenheimer Complex reaction involves a Meisenheimer complex intermediate O

+N O slow, rate - determining Cl + Nu (1) NO2 O +N O Cl Nu NO2 fast (2) O +N

O Nu + :Cl NO2 A Meisenheimer complex 21-45 21 Prob 21.7 Write a mechanism for each reaction. Cl (a) + (b) (c) (d) Cl

+ O O + FeCl3 Cl2 AlCl3 SnCl4 Cl + CH2 Cl2 + 2HCl AlCl3 + 2HCl O O + 2HCl

+ 2HCl 21-46 21 Prob 21.8 Offer an explanation for the preferential nitration of pyridine in the 3 position rather than the 2 position. N Pyridine + HNO3 NO2 H2 SO4 300C N + H2 O 3-Nitropyridine 21-47

21 Prob 21.9 Offer an explanation for the preferential nitration of pyrrole in the 2 position rather than in the 3 position. + N H Pyrrole HNO3 CH3 COOH 5C + NO2 N H 2-Nitropyrrole H2 O 21-48 21 Prob 21.15 Predict the major product(s) from treatment of each compound with HNO3/H2SO4.

OCH3 (a) NO2 (b) CH3 NO2 NO2 CH3 (c) (d) OH 21-49 21 Prob 21.16 Account for the fact that N-phenylacetamide is less reactive toward electrophilic aromatic substitution than aniline. O NHCCH3 N-Phenylacetamide

(Acetanilide) NH2 Aniline 21-50 21 Prob 21.17 Propose an explanation for the fact that the trifluoromethyl group is meta directing. CF3 CF3 + HNO3 H2 SO4 + H2 O NO2 21-51 21 Prob 21.19 Arrange the compounds in each set in order of decreasing reactivity toward electrophilic aromatic substitution. O

O (a) OCCH3 (A) (b) COCH3 (C) (B) NO2 (A) COOH (B) (C) 21-52 21 Prob 21.19 (contd) Arrange the compounds in each set in order of decreasing reactivity toward electrophilic aromatic substitution.

(c) CH3 (A) (d) (B) Cl (A) (e) CH2 Cl C N (B) NH2 (A) O NHCCH3 (B)

CHCl2 (C) OCH2 CH3 (C) O CNHCH3 (C) 21-53 21 Prob 21.20 Draw a structural formula for the major product of nitration of each compound. O NHCCH3 OCH3 (a) (b) (c) CH3 CH3

O CCH3 (f) COOH CH3 SO3 H (d) Cl CH3 (e) COOH (g) OCH3 COOH NO2 (h)

Cl NHCCH3 O 21-54 21 Prob 21.21 Which ring in each compound undergoes electrophilic aromatic substitution more readily? Draw the product of nitration of each compound. (a) O CNH (b)O2 N (c) O CO 21-55 21 Prob 21.22 Propose a mechanism for the formation of bisphenol A. 2

O OH + CH3 CCH3 H3 PO4 CH3 HO C OH + H2 O CH3 Bisphenol A 21-56 21 Prob 21.23 Propose a mechanism for the formation of BHT. OH OH +

H3PO4 4-Methylphenol 2-Methyl(p-Cresol) propene 2,6-Di-tert-butyl-4-methylphenol "Butylated hydroxytoluene" (BHT) 21-57 21 Prob 21.24 Propose a mechanism for the formation of DDT. 2 O H SO 2 4 Cl + Cl3CCH Chlorobenzene Trichloroacetaldehyde Cl CH CCl3 DDT

Cl + H2 O 21-58 21 Prob 21.27 Propose a mechanism for this reaction. O + O O H3 PO4 O Succinic anhydride COOH 4-Oxo-4-phenylbutanoic acid 21-59 21 Prob 21.28 Account for the regioselectivity of the nitration in Step 1,

and propose a mechanism for Step 2. Cl Cl HNO3 (1) CF3 O2N NO2 CF3 N H (2) N O2N NO2 CF3 Trifluralin B 21-60

21 Prob 21.29 Propose a mechanism for the displacement of chlorine by (1) the NH2 group of the dye and (2) an -OH group of cotton. Cl N Cl N N Dye-NH2 Cl O-cotton Cl Cyanuryl chloride N N HO-cotton Dye-NH N Cl A reactive dye

N N Dye-NH N O-cotton Dye covalently bonded to cotton 21-61 21 Prob 21.31 Show how to prepare (a) and (b) from 1-phenyl-1propanone. O O O Br Br 1-Phenyl-1-propanone (Propiophenone) (a) (b)

21-62 21 Prob 21.33 Show how to bring about each conversion. CH3 COOH (a) OH OCH2 CH3 (b) COOH Cl (c) OCH3 NO2 OCH3 (d)

NO2 CH2 CH3 CH=CH2 O2 N OCH3 CCH3 O (e) 21-63 21 Prob 21.35 Propose a synthesis for each compound from benzene. H N (a) (b) Cl O

Cl 21-64 21 Prob 21.36 Propose a synthesis of 2,4-D from chloroacetic acid and phenol. O COOH OH Cl OH Cl Cl COOH + Cl 2,4-Dichlorophenoxyacetic acid (2,4-D) Cl

Chloroacetic acid Phenol 21-65 21 Prob 21.41 Propose a synthesis of this compound from benzene. O 4-Isopropylacetophenone 21-66 21 Prob 21.42 Propose a synthesis of this compound from 3methylphenol. O2 N NO2 OCH3 21-67 21 Prob 21.43 Propose a synthesis of this compound from toluene and phenol.

NH2 O Br O Cl 21-68 21 Prob 21.44 Propose a mechanism for this example of chloromethylation (introduction of a CH2Cl group on an aromatic ring). Show how to convert the product of chloromethylation to piperonal. + CH2 O + HCl O O chloromethylation CHO CH2 Cl ? O

O O O Piperonal 21-69 21 Prob 21.45 Given this retrosynthetic analysis, propose a synthesis for Dinocap from phenol and 1-octene. Hexyl O O O2N NO2 Dinocap Hexyl OH (1) O2N

(2) NO2 OH O2N (3) OH NO2 21-70 21 Prob 21.46 Show how to synthesize this trichloro derivative of toluene from toluene. N Cl N Cl Cl Cl

O Cl Cl Miconazole Cl 2,4-Dichloro-1chloromethylbenzene CH3 Toluene 21-71 21 Prob 21.47 Given this retrosynthetic analysis, propose a synthesis for bupropion. O Cl H N O Cl

Br Bupropion O Cl 21-72 21 Aromatics II End Chapter 21 21-73

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