TOPIC 2. REACTIONS OF AROMATIC COMPOUNDS (Chapters 15, parts of 20, and 21)

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1 L TPIC 2. REACTINS F ARMATIC CMPUNDS (Chapters 15, parts of 20, and 21) Add e.g. of SNAr, replace aniline example, turn BT into and example

Describe the reactions of anilines (ArN 2 ) and phenols (Ar) which take place on the nucleophilic ring or nucleophilic substituent. 3.

2 L TPIC 2. TC PAIN KILLERS BJECTIVES 1. Describe the reactions between strong electrophiles and aromatic compounds (the nucleophilc component) which lead to substitution of a hydrogen atom on the aromatic ring. 2. Describe the reactions of anilines (ArN 2 ) and phenols (Ar) which take place on the nucleophilic ring or nucleophilic substituent. 3. utline the mechanisms whereby aryl halides undergo nucleophilic substitution (NT S N 1 or S N 2) 4. Describe various reactions of the side chain of aromatic compounds. 5. Use this knowledge to predict the products of these reactions and to be able to do single-step syntheses and multi-step syntheses using these reactions as well as the reactions previously studied.

3 ELECTRPILIC ARMATIC SUBSTITUTIN REACTINS Electrophilic Substitution versus Addition Arenes undergo substitution with strong electrophiles + E-A catalyst E=electrophile; A=anion or leaving group E-A + catalyst active electrophile S: Review Prob: 15.28,30 E =, Br N 2 S 3 R C(=)R + Br-Br FeBr 3 whereas alkenes undergo addition reactions + Br-Br Br Br Electrophilic aromatic substitutions alogenation al 2 Feal 3 or Fe Nitration N 3 2 S 4 Sulfonation S 3 2 S 4 fuming sulfuric acid

4 Friedel-Crafts Alkylation R-al Al 3 Friedel-Crafts Acylation R Al 3 Mechanism First step E Compare to: E E E E

5 Second step Consider two possibilities Compare to: A A E A E ALGENATIN F BENZENE S:15.3 Role of the catalyst (bromine as example): Generation of Active Electrophile Br Br FeBr 3 Br Br FeBr 3 Nu Br Nu Br Br FeBr 3

6 Mechanism of Substitution Step Br Br FeBr 3 Br Br FeBr 3 Br FeBr 3 NITRATIN F BENZENE S:15.4 Role of the Catalyst: Generation of Active Electrophile 3 S N N

Mechanism of Substitution Step N N 2 N3 2 S 4 Nitrobenzene N 2 N 2 2

7 Mechanism of Substitution Step N N 2 N3 2 S 4 Nitrobenzene N 2 N o C [Ni] 600 o C Nitrobenzene is an aryl organic compound used primarily to manufacture aniline. This compound is used for several purposes including the manufacture of polyurethane, acetaminophen, and chemical dyes.

8 SULFNATIN F BENZENE Generation of Active Electrophile 2 S 4 Mechanism of Substitution Step S S:15.5 S 3 S 3 S 3 S 2 - S 3? Prob: 15.18,30?

L FRIEDEL-CRAFTS ALKYLATIN S:15.6 Prob: 15.

9 L FRIEDEL-CRAFTS ALKYLATIN S:15.6 Prob: a,b Examples + F + 2 S 4 + Al 3 An Industrial Friedel-Crafts Reaction 2 C C 2 F dehydrogenation While practiced in industry under carefully controlled conditions, this process is difficult to control with the potential for polyalkylation. In addition, the dehydrogenation reaction is unusual, and not possible with other alkanes styrene RR Radical polymerization n polystyrene

10 Role of the Catalyst: Generation of Active Electrophile Alkene + strong acid R Alcohol + strong acid R Alkyl chloride + Lewis acid R Al Mechanism of Substitution Step R R Al R + + Al 3 Al 3

11 Rearrangement during Friedel-Crafts Alkylation + Al 3 FRIEDEL-CRAFTS ACYLATIN S:15.7 Examples + C 3 1. Al C 3 C 3 1. Al

12 Role of the Catalyst: Generation of Active Electrophile R Al Al R R Mechanism of Substitution Step R C R Al R + + Al 3 Al 3

13 LIMITATINS F FRIEDEL-CRAFTS ALKYLATINS AND ACYLATINS S:15.8,9 Prob: 15.29cd;33 1. Rearrangements to more stable carbocations (1 2 or 3 ; 2 3 ) + Al 3 2. Vinyl, alkynyl and aryl halides do not serve as electrophiles + Al 3 3. Polyalkyation can occur (will discuss later) R R 4. R Cannot make aldehydes or carboxylic acids cannot use: C C 5. Benzene with electron withdrawing groups are poor nucleophiles -N 2 alkylation Y -C 2 or acylation -CR (see later) Y= - + NR 3 -CF 3 -S 3 6. Lewis bases complex the Lewis acid and hinder reaction + Al 3 NR 2 + Al 3 7. Di-, tri( )-haloalkanes Al 3

14 A Solution to the Problem of Rearrangements During Friedel-Crafts Alkylations Problem: Rearrangement + Al 3 Solution: Acylation followed by emmensen Reduction + Al 3 R= or alkyl Zn(g) heat Problem: ow would you prepare 1-phenyl-2-methylbutane??

15 Problem: ow would you prepare 2-phenyl-2-butanol??? Prob: 15.29,33?

16 L EFFECT F SUBSTITUENTS N REACTIVITY AND RIENTATIN Effect of Substituents on RATE of substitution e.g. Relative rates for nitration C 3 C 3 N 2 S:15.10 Prob:15.26,27, 31,32,34, Electron donating groups Resonance donors -Y: (except halogens), e.g. -R and -NR 2 Inductive donors -alkyl Electron withdrawing groups Resonance withdrawing -X=Y Inductive withdrawing -al, -CF 3 Why do substituents effect the rate of S E Ar reactions? I R energy (reactivity) of reactants E a rate EDG increase the nucleophilicity of the benzene ring faster reaction EWG decrease the nucleophilicity of the benzene ring slower reaction energy (reactivity) of intermediates E a rate EDG decrease the energy of the carbocation intermediate faster reaction EWG increase the energy of the carbocation intermediate slower reaction P

17 Effect of Substituents on PSTIN of substitution Substituents direct the substitution reaction X to different positions o - ortho p - para m - meta 1. Activating ortho/para directors C 3 C 3 C 3 C 3 N 3 N 2 2 S 4 N 2 N 2 25 times more reactive than benzene 59 % 4 % 37 % Type of substituents which are activating o/p directors: -alkyl and -Y: (not halogen), e.g. -R and -NR 2 C 3 Y Y

18 2. Deactivating ortho-para directors N 3 N 2 2 S 4 N 2 N 2 30 times less reactive than benzene 30 % 1% 69 % Type of substituents which are deactivating o/p directors: -F, -, -Br, -I al al al 3. Deactivating meta directors N 2 N0 3 N 2 N 2 N 2 N 2 2 S 4 N 2 N times less reactive than benzene 6 % 93% 1 % Types of substituents which are deactivating m directors: general δ+ δ X Y and CF 3 e.g. C N R (there are no activating m directing substituents) N

19 Understanding the Basis for Substituent Effects on Electrophilic Aromatic Substitution S:15.11 Analysis 1: Consider the effect of Q on the stability of the intermediate cyclohexadienyl cation. Q E Q Q Q E E E ortho meta para Resonance structures of cyclohexadienyl cation from ortho attack: Q E Q E Q E Q E A B C C C Resonance structure A is especially stabilized by electron donating substituents, increasing the rate of reaction at this position. C -C 3 Resonance structure A is especially destabilized by electron withdrawing substituents, decreasing the rate of reaction at this position C C N C N» Electron donating substituents facilitate substitution at the ortho positions.

20 Resonance structure of cyclohexadienyl cation from meta attack: Q Q Q Q E E E E» Electron donating substituents do not facilitate substitution at the meta position. Resonance structures of cyclohexadienyl cation from para attack: Q Q Q Q E E» Electron donating substituents facilitate substitution at the para position. E E»» Electron donating groups are o/p- directing If the substituent is electron donating (e.g. alkyl [hyperconjugation] or oxygen (::) or nitrogen (N:) [resonance donating]), the resonance structures from ortho and para attack are stabilized compared to the meta position. This leads to a faster overall reaction, favoring substitution at the ortho and para positions. C 3 E If the substituent is electron withdrawing (e.g. -N 2 or -CR [resonance] or -CF 3 [inductive]) the resonance structures from attack at all positions are destabilized. This leads a slower overall reaction. Those resonance structures from ortho and para attack are particularly destabilized. This disfavors substitution at these positions, leading to meta substitution. N E

21 Analysis 2: Consider the effect of the substituent on the electron distribution in the starting material C 3 C 3 N N» Electron donating groups are o/p- directing» alogen substituents are o/p- directing» Electron withdrawing groups are m- directing Summary of Activating and Directing Effects All m- directors are deactivators All o/p- directors, except halogens, are activators Strong electron withdrawing groups Weak electron withdrawing groups Weak electron donating groups Strong electron donating groups -S 3 -CN -N 2 -C()X (X=,R,,R) -CF 3 -al Inductive withdrawal Deactivating N -R R R -R() -NR() 2 Deactivating meta-directing Resonance donation ortho/para-directing Activating ortho/para-directing Activating ortho/para-directing

22 Directing effects on monosubstituted rings C 3 Br 2 C 3 AlBr 3 C 3 Br 2, cold acetic acid C 3 CF 3 N 3 CF 3 2 S 4 Br Br N 3 2 S 4 Br 2 FeBr 3 C 3 I Al 3

23 Directing Effects on Disubstituted Rings C 3 C 3 C Al 3 C 3 C 3 C 3 C 3 Br 2 FeBr 3 C 3 N 2 N 2 Steric effects C 3 N 3 2 S 4 C 3 C(C 3 ) 3 C(C 3 ) 3 C 3 N 3 C 3 C 3 2 S 4 C 3 When directing effects are in competition with one another C 3 C 3 Br 2 Ac C 3 C 3

24 Trinitrotoluene (TNT) 2 S 4 2 N N 2 N 3 N 2 1,4-Dichlorobenzene 2 Fe 3

25 ? Prob: 15.26,27,31,32,34,35? L SYNTETIC APPLICATINS Consider how each substituent can be either: 1. Introduced by electrophilic substitution -al, -S 3, -N 2, -R, -CR S:15.14 Prob:15.29e-m, 38,41,43,45, 48,50,51,53 or 2. Prepared by modification of an existing substituent -C 2 from R -C 2 R from CR -C 2 Br from C 3 -C 2 from C 2 Br Consider whether reactions can really be performed: Directing effects of other substituents Effect of reagents/conditions on other substituents Think RETRSYNTETICALLY!

26 Problem [Solomons 15.29l) - ow would you prepare 2-chloronitrobenzene? N 2? Problem - 3-Chloroethylbenzene has two o/p-directors meta to one another. ow can it be synthesized??

27 Problem - 4-Nitrobenzoic acid has two m-directors para to one another. ow can it be synthesized? C 2? N 2? Prob: 15.29e-m,38,41,43,45,48,51,53?

28 ANILINES: SYNTESIS, BASICITY AND NUCLEPILICITY Synthesis of Anilines: Reduction of Nitrobenzenes S:20.5B N 2 N 2 N 3 2 S 1.Fe,; or 2 /Pt or 2 S, N 3,Et Challenges with Electrophilic Aromatic Substitutions of Anilines Attempts to Perform Friedel-Crafts Acylations N 2 Br2 Attempts to Perform Nitrations N 2 N 3 Attempts to Perform alogenations N 2 C3C

29 Using N-Acylation to Moderate Nucleophilicity of the Ring ARYLDIAZNIUM SALTS S: Prob:20.26,31 Formation: Reaction of Anilines with Nitrous Acid N 2 NaN 2 cold

30 Substitution Reactions of Arene Diazonium Salts Br F 1. BF 4 2. Δ Cu, Cu 2+ 2 Cu 3 P 2, 2 N N CuBr CuCN KI I CN Designing Syntheses via Aromatic Diazonium Salts? Problem - 3-Chlorophenol has two o/p directors meta to one another. Either substituent can be introduced by use of diazonium salts. The diazonium substituent is prepared from the nitro substituent (via the amine), which is a meta director. ow can 3-chlorophenol be prepared?

31 Problem 1,3,5-Tribromobenzene has three o/p directors meta to one another. ow can 1,3,5-tribromobenzene be prepared?? Br Br Br Diazo coupling of diazonium salts with electron-rich arenes EDG EDG= -X, not -al N N

32 Eriochrome Black T - Sodium (4Z)-4-[(1-hydroxynaphthalen-2-yl)hydrazinylidene]- N S 3 N N 2 Eriochrome Black T is an azo dye indicator that is used in titrations, most commonly the process to determine water hardness. In its protonated form it is blue and it turns red when it complexes with calcium, magnesium, or other metal ions. S 3 N N N 2? Prob: 15.26,31?

33 Introduction PENLS S: rob: oxygen: nucleophilic ring (o-,p- positions): nucleophilic Synthesis of phenols by hydrolysis of aryldiazonium salts Ar Ar N 2 Ar N 2 Ar N N Ar Industrial preparation of phenol and acetone cat. Friedel Crafts alkylation 2 Δ 2 S 4 benzylic oxidation hydrolytic rearrangement benzene cumene phenol acetone +

34 Acidity of Phenols + B + B pk a = 9.9 Compare to cyclohexanol: pk a = 18 Electron withdrawing groups, -X=Y: stabilize the conjugate base stronger acid N N N... Acid strength > > > CC 3 CN C 3 o- or p-ewg m-ewg o- or p-edg

35 REACTINS F PENL: NUCLEPILIC XYGEN S:21.6,7 Prob Na 2 2. RBr Williamson ether synthesis R Esterification: see later N REACTINS F PENL: NUCLEPILIC RING S:21.8 Br 2 N 3 2 S 4

36 BT - Butylated ydroxy Toluene Synthesis BT p-cresol Anti-oxidative action + R. Tylenol - Acetaminophen N

37 Synthesis of Aspirin 1. Na 2. C 2 3. (C 3 C) 2 Mechanism Na Na C TE CLAISEN REARRANGEMENT Na Δ Br S:21.9

38 ? Prob: 21.13,16? Reduction XIDATIN AND REDUCTIN F TE ARMATIC RINGS S: / Ni heat pressure + 2Na + 2Et N 3 N 3 Na, Et

39 xidation Electron Rich Arenes [] N 2 [] N N n ydroquinones and Quinones [] [] L ARYL ALIDES AND NUCLEPILIC ARMATIC SUBSTITUTIN Comparison of ydrolysis Reactions 2 rt S rt Na 350 o C

40 Nucleophilic Aromatic Substitution take place primarily in two cases: 1. The presence of a strong electron withdrawing group o- or p- to the leaving group 2. The presence of a strong base and a hydrogen adjacent to the leaving group Scenario 1: Presence of Strong Electron Withdrawing Groups Relative rates of hydrolysis effect of o/p EWG N 2 N 2 N 2 k rel 1 7 x x Rate = k[substrate][nucleophile]

41 Relative rates of hydrolysis effect of halide F Br I N 2 N 2 N 2 N 2 k rel Wrong Mechanisms Disproven by Experimental Data al Nu N 2 N 2 Nu al N 2

42 Mechanism Consistent with Experimental Data Nu al N N N N Scenario 2: Effect of a very strong base in the absence of EWG verall Reaction NaN 2 N 3

43 ther Experimental bservations NaN 2 N 3 C 3 13 C NaN 2 N 3 Mechanism - Consistent with Experimental Data NaN 2

Problem: 2,4,5-Trichlorophenoxyacetic acid (4,5-T, Agent range). ow could 2,4,5-T be prepared from 2,4,5-trichlorophenol?? Problem: Dioxins are polychloroinated dibenzodioxanes.

44 Problem: 2,4,5-Trichlorophenoxyacetic acid (4,5-T, Agent range). ow could 2,4,5-T be prepared from 2,4,5-trichlorophenol?? Problem: Dioxins are polychloroinated dibenzodioxanes. They are extremely toxic. 2,3,7,8-TCDD, a dioxin, is formed during the production? of 2,4,5-T. Provide a mechanism for its formation. PLANET/TML/peril_toxins.html

45 L REVIEW: ELECTRPILIC ARMATIC SUBSTITUTIN Reactions alogenation Nitration Sulfonation Friedel-Crafts alkylation Frieldel-Crafts acylation Activating/Deactivating and Directing effects Deactivating meta-directing Deactivating ortho/para-directing Activating ortho/para-directing -CN -N 2 -C()X (X=R,,R) -al -R Activating ortho/para-directing -(R) -N(R) 2 -CF 3 Modification of Side chains -C 2 from R -C 2 R from CR -C 2 Br from C 3 -C 2 from C 2 Br Anilines in Synthesis N 2 N 2 N 2 X Y m-directing o/p-directing Y= al,, CN,

46 Problem [Solomons 15.31d] - Propose a synthesis of 4-bromobenzoic acid from toluene? C 2 Br Problem [Solomons 15.31a] - Propose a synthesis of m-chlorobenzoic acid from toluene? C 2

47 Problem [Solomons 15.32c] - Propose a synthesis of 2-bromo-4- nitroaniline from aniline. N 2 Br? N 2 Problem [Solomons 15.43a] - Propose a synthesis of the following molecule from benzene?

48 TPIC 2 N EXAM 2 Types of Questions - Predict product of reactions S E Ar, S N Ar, reactions of substituents, diazonium salts - Mechanisms - S E Ar (incl. generation of electrophile), S N Ar (two pathways) - The effect of substituents: rate of reactions, directing effects, relative acidity/basicity of phenols and anilines - Design of multistep syntheses (including use of reactions from organic-i and earlier in semester) Provide mechanistic rationale for experimental observations; use knowledge of mechanism to predict the outcome and pathways of reactions Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 2 - Get up-to-date NW! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the Learning Group Problem at the end of the chapter.

TOPIC 2. REACTIONS OF AROMATIC COMPOUNDS (Chapters 15, parts of 20, and 21)

TOPIC 2. REACTIONS OF AROMATIC COMPOUNDS (Chapters 15, parts of 20, and 21) L TPIC 2. RACTINS F ARMATIC CMPUNDS (Chapters 15, parts of 20, and 21) BJCTIVS 1. Describe the reactions between strong electrophiles and aromatic compounds (the nucleophilc component) which lead to substitution