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

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1 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 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. CM2312:

2 LCTRPILIC ARMATIC SUBSTITUTIN RACTINS lectrophilic Substitution versus Addition S: Review Prob: 15.28,30 Arenes undergo substitution with strong electrophiles catalyst + -A =electrophile; A=anion or leaving group -A + catalyst active electrophile + Br-Br FeBr 3 whereas alkenes undergo addition reactions + Br-Br Br Br lectrophilic aromatic substitutions alogenation al 2 Feal 3 or Fe Nitration N 3 2 S 4 Sulfonation S 3 2 S 4 CM2312:

3 Friedel-Crafts Alkylation R-al Al 3 Friedel-Crafts Acylation R Al 3 Mechanism First step Compare to: CM2312:

4 Second step Consider two possibilities Compare to: A A A ALGNATIN F BNZN S:15.3 Role of the catalyst (bromine as example): Generation of Active lectrophile Br Br FeBr 3 Br Br FeBr 3 Nu Br Nu Br Br FeBr 3 CM2312:

5 Mechanism of Substitution Step Br Br FeBr 3 Br Br FeBr 3 NITRATIN F BNZN S:15.4 Role of the Catalyst: Generation of Active lectrophile 3 S N N CM2312:

6 Mechanism of Substitution Step N N 2 SULFNATIN F BNZN Generation of Active lectrophile 2 S 4 Mechanism of Substitution Step S S:15.5 S 3 S 3 S 3 S 2 - S 3 CM2312:

7 ? Prob: 15.18,30? L FRIDL-CRAFTS ALKYLATIN S:15.6 Prob: a,b xamples + F + 2 S 4 + Al 3 CM2312:

8 Role of the Catalyst: Generation of Active lectrophile Alkene + strong acid R Alcohol + strong acid R Alkyl chloride + Lewis acid R Al Mechanism of Substitution Step R R Al R + + Al 3 CM2312:

9 Rearrangement during Friedel-Crafts Alkylation + Al 3 FRIDL-CRAFTS ACYLATIN S:15.7 xamples + 3 C 1. Al R R 1. Al CM2312:

10 Role of the Catalyst: Generation of Active lectrophile R Al Al R R Mechanism of Substitution Step R C R Al R + + Al 3 CM2312:

11 LIMITATINS F FRIDL-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 CM2312:

12 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 R Zn(g) heat Problem: ow would you prepare 1-phenyl-2-methylbutane?? CM2312:

13 Problem: ow would you prepare 2-phenyl-2-butanol??? Prob: 15.29,33? CM2312:

14 L FFCT F SUBSTITUNTS N RACTIVITY AND RINTATIN ffect of Substituents on RAT of substitution e.g. Relative rates for nitration C 3 C 3 N 2 S:15.10 Prob:15.26,27, 31,32,34, lectron donating groups Resonance donors -Y: (except halogens), e.g. -R and -NR 2 Inductive donors -alkyl lectron withdrawing groups Resonance withdrawing -X=Y Inductive withdrawing -al, -CF 3 Why do substituents effect the rate of S Ar reactions? I R P energy (reactivity) of reactants a rate DG increase the nucleophilicity of the benzene ring faster reaction WG decrease the nucleophilicity of the benzene ring slower reaction energy (reactivity) of intermediates a rate DG decrease the energy of the carbocation intermediate faster reaction WG increase the energy of the carbocation intermediate slower reaction CM2312:

15 ffect 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 CM2312:

16 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 CM2312:

17 Understanding the Basis for Substituent ffects on lectrophilic Aromatic Substitution S:15.11 Analysis 1: Consider the effect of Q on the stability of the intermediate cyclohexadienyl cation. Q Q Q Q ortho meta para Resonance structures of cyclohexadienyl cation from ortho attack: Q Q Q Q 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» lectron donating substituents facilitate substitution at the ortho positions. CM2312:

18 Resonance structure of cyclohexadienyl cation from meta attack: Q Q Q Q» lectron donating substituents do not facilitate substitution at the meta position. Resonance structures of cyclohexadienyl cation from para attack: Q Q Q Q» lectron donating substituents facilitate substitution at the para position.»» lectron 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 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 CM2312:

19 Analysis 2: Consider the effect of the substituent on the electron distribution in the starting material C 3 C 3 N N» lectron donating groups are o/p- directing» alogen substituents are o/p- directing» lectron withdrawing groups are m- directing Summary of Activating and Directing ffects 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 CM2312:

20 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 Al 3 Br 2 FeBr 3 C 3 I Al 3 CM2312:

21 Directing ffects 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 2 S 4 C 3 C 3 When directing effects are in competition with one another C 3 C 3 Br 2 Ac C 3 C 3 CM2312:

22 ? Prob: 15.26,27,31,32,34,35? L SYNTTIC 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 ffect of reagents/conditions on other substituents Think RTRSYNTTICALLY! CM2312:

23 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?? CM2312:

24 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? CM2312:

25 ANILINS: SYNTSIS, BASICITY AND NUCLPILICITY 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,t Challenges with lectrophilic 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 CM2312:

26 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 CM2312:

27 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. ither 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? CM2312:

28 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 DG DG= -X, not -al N N CM2312:

29 ? Prob: 15.26,31? Introduction PNLS S: rob: oxygen: nucleophilic ring (o-,p- positions): nucleophilic phenoxide: -: resonance stabilized acidic CM2312:

30 Synthesis of phenols by hydrolysis of aryldiazonium salts Ar N 2 Ar N N Ar Industrial preparation of phenol and acetone cat. Friedel Crafts alkylation also 2 Δ 2 S 4 benzylic oxidation 2 Fe hydrolytic rearrangement Na high temperature + Acidity of Phenols + B + B pk a = 9.9 Compare to cyclohexanol: pk a = 18 CM2312:

31 lectron withdrawing groups, -X=Y: stabilize the conjugate base stronger acid N N N... Acid strength > > > CC 3 CN C 3 o- or p-wg m-wg o- or p-dg RACTINS F PNL: NUCLPILIC XYGN S:21.6,7 Prob Na 2 2. RBr Williamson ether synthesis R sterification: see later N CM2312:

32 RACTINS F PNL: NUCLPILIC RING S:21.8 Br 2 N 3 2 S 4 BT - Butylated ydroxy Toluene Synthesis BT p-cresol Anti-oxidative action + R. CM2312:

33 Tylenol - Acetaminophen N Synthesis of Aspirin 1. Na 2. C 2 3. (C 3 C) 2 Mechanism Na Na C CM2312:

34 T CLAISN RARRANGMNT Na Δ Br S:21.9? Prob: 21.13,16? CM2312:

35 Reduction XIDATIN AND RDUCTIN F T ARMATIC RINGS S: / Ni heat pressure + 2Na + 2t N 3 N 3 Na, t xidation lectron Rich Arenes [] N 2 [] N N n ydroquinones and Quinones [] [] CM2312:

36 L ARYL ALIDS AND NUCLPILIC ARMATIC SUBSTITUTIN Comparison of ydrolysis Reactions S rt 2 rt Na 350 o C 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 CM2312:

37 Scenario 1: Presence of Strong lectron Withdrawing Groups Relative rates of hydrolysis effect of o/p WG N 2 N 2 N 2 k rel 1 7 x x Rate = k[substrate][nucleophile] Relative rates of hydrolysis effect of halide F Br I N 2 N 2 N 2 N 2 k rel CM2312:

38 Wrong Mechanisms Disproven by xperimental Data al Nu N 2 N 2 Nu al N 2 Mechanism Consistent with xperimental Data Nu al N N N N CM2312:

39 Scenario 2: ffect of a very strong base in the absence of WG verall Reaction NaN 2 N 3 ther xperimental bservations NaN 2 N 3 C 3 13 C NaN 2 N 3 CM2312:

40 Mechanism - Consistent with xperimental 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?? CM2312:

24] Toliprolol, a β-blocker, is prepared by the following scheme. What is the structure of toliprolol and the? synthetic intermediates?

41 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. PLANT/TML/peril_toxins.html Problem [Solomons 21.24] Toliprolol, a β-blocker, is prepared by the following scheme. What is the structure of toliprolol and the? synthetic intermediates? (C 3 ) 2 CN 2 C C Toliprolol, C N 2 C 3 rg/amrt/index.html graines.asp CM2312:

42 L RVIW: LCTRPILIC 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, CM2312:

43 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 CM2312:

44 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? CM2312:

Synthesis of Ibuprofen C 2 http://www.heartinfo.com/features/analgesics/analgesic.

generation of electrophile) - Predict the relative acidity/basicity of substituted phenols and anilines - Design of multistep syntheses (including use of reactions from organic-i) - Provide

45 Synthesis of Ibuprofen C 2 TPIC 2 N XAM 2 Types of Questions - Directing effects - Predict the product of reactions S Ar, reactions of substituents, diazonium salts - Mechanisms - S Ar (incl. generation of electrophile) - Predict the relative acidity/basicity of substituted phenols and anilines - Design of multistep syntheses (including use of reactions from organic-i) - Provide mechanistic rationale for experimental observations; use knowledge of mechanism to predict products Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for xam 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. CM2312:

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