Explain the reactivity and orientation effects observed in each heterocycle. E+ E E + E

Why is benzene less reactive towards electrophiles than an alkene, even though it has more electrons than an alkene (six versus two)?

In Step [2] of Mechanism 18.1, loss of a proton to form the substitution product was drawn using one resonance structure only. Use curved arrows to show how the other two resonance structures can be converted to the substitution product (PhE) by removal of a proton with :B.

Draw a detailed mechanism for the chlorination of benzene using Cl2 and FeCl3.

Draw a stepwise mechanism for the sulfonation of an alkyl benzene such as A to form a substituted benzenesulfonic acid B. Treatment of B with base forms a sodium salt C that can be used as a synthetic detergent to clean away dirt (see Problem 3.15). SO3 H2SO4 SO3H A NaOH B SO3 Na+ synthetic detergent C

What product is formed when benzene is treated with each organic halide in the presence of AlCl3? a. (CH3)2CHCl b. Cl c. CH3CH2 Cl C O

What acid chloride would be needed to prepare each of the following ketones from benzene using a FriedelCrafts acylation? a. C O CH2CH2CH(CH3)2 b. O C c. C O

Draw a stepwise mechanism for the FriedelCrafts alkylation of benzene with CH3CH2Cl and AlCl3.

Which halides are unreactive in a FriedelCrafts alkylation reaction? a. Br b. Br c. Br d. Br

Draw a stepwise mechanism for the following reaction. AlCl3 (CH3) + 2CHCH2Cl + HCl C(CH3)3

Draw the product of each reaction. a. + H2SO4 c. + OH H2SO4 b. (CH3) + 2C H2SO4 CH2 d. + H2SO4 OH

Draw a stepwise mechanism for the intramolecular FriedelCrafts acylation of compound A to form B. B can be converted in one step to the antidepressant sertraline (trade name Zoloft). CI CI AICI3 NHCH3 CI O A CI CI one step O B CI CI sertraline (Zoloft)

Intramolecular reactions are also observed in FriedelCrafts alkylation. Draw the intramolecular alkylation product formed from each of the following reactants. (Watch out for rearrangements!) a. b. OH c. Cl

Which substituents have an electron-withdrawing and which have an electron-donating inductive effect: (a) CH3CH2CH2CH2 ; (b) Br ; (c) CH3CH2O ?

Draw all resonance structures for each compound and use the resonance structures to determine if the substituent has an electron-donating or electron-withdrawing resonance effect. a. OCH3 b. CH3 O C

Classify each substituent as electron donating or electron withdrawing. a. OCH3 b. I c. C(CH3)3

Draw the products of each reaction. a. OCH3 CH3CH2Cl AlCl3 b. Br HNO3 H2SO4 c. NO2 Cl2 FeCl3

Draw the products formed when each compound is treated with HNO3 and H2SO4. State whether the reaction occurs faster or slower than a similar reaction with benzene. a. COCH3 b. CN c. OH d. Cl e. CH2CH3

Label each compound as more or less reactive than benzene in electrophilic aromatic substitution. a. C(CH3)3 b. OH OH c. COOCH2CH3 d. + N(CH3)3

Draw all resonance structures for the carbocation formed by ortho attack of the electrophile + NO2 on each starting material. Label any resonance structures that are especially stable or unstable. a. C(CH3)3 b. OH c. CHO

Use the procedure illustrated in Sections 18.9AC to show why chlorine is an ortho, para director

Draw the products of each reaction. a. Cl2 OH FeCl3 b. Cl2 OH c. CH3 Cl2 FeCl3

Which of the following compounds undergo FriedelCrafts alkylation with CH3Cl and AlCl3? Draw the products formed when a reaction occurs. a. SO3H b. Cl c. N(CH3)2 d. NHCOCH3

Draw the products formed when each compound is treated with HNO3 and H2SO4. a. OCH3 COOCH3 b. OCH3 Br c. CH3 NO2 d. Cl Br

Devise a synthesis of each compound from the indicated starting material. a. Cl SO3H b. O2N C CH3 O c. OH Br CH3 OH

Explain why C6H5CH2CH2Br is not formed during the radical bromination of C6H5CH2CH3.

Draw the products formed when isopropylbenzene [C6H5CH(CH3)2] is treated with each reagent: (a) Br2, FeBr3; (b) Br2, h; (c) Cl2, FeCl3.

How could you use ethylbenzene to prepare each compound? More than one step is required. a. Br b. OH c. O d. OH

What steps are needed to convert benzene into p-isobutylacetophenone, a synthetic intermediate used in the synthesis of the anti-infl ammatory agent ibuprofen. several steps O p-isobutylacetophenone COOH ibuprofen

Only one alkyl benzene with the general structure C6H5CH2R can be made by both FriedelCrafts alkylation and FriedelCrafts acylation followed by reduction. What is the identity of R in this compound?

Synthesize each compound from benzene. a. COOH b. NH2 c. COOH Br

Synthesize each compound from benzene. a. C CH2CH3 SO3H O CH3 b. CH2CH3 Br c. CHO CI

Draw the products formed when phenol (C6H5OH) is treated with each reagent. a. HNO3, H2SO4 g. Cl2, FeCl3 b. SO3, H2SO4 h. product in (a), then Sn, HCl c. CH3CH2Cl, AlCl3 i. product in (d), then Zn(Hg), HCl d. (CH3CH2)2CHCOCl, AlCl3 j. product in (d), then NH2NH2, OH e. Br2, FeBr3 k. product in (c), then Br2, h f. Br2 l. product in (c), then KMnO4

Draw the products formed when benzonitrile (C6H5CN) is treated with each reagent. a. Br2, FeBr3 b. HNO3, H2SO4 c. SO3, H2SO4 d. CH3CH2CH2Cl, AlCl3 e. CH3COCl, AlCl3

Draw the products formed when benzonitrile (C6H5CN) is treated with each reagent. a. Br2, FeBr3 b. HNO3, H2SO4 c. SO3, H2SO4 d. CH3CH2CH2Cl, AlCl3 e. CH3COCl, AlCl3

Draw the products of each reaction. a. HO NO2 HNO3 H2SO4 e. C NHCOCH3 CH3COCl AlCl3 O C CH3O b. CH3 OH SO3 H2SO4 f. NO2 NO2 HNO3 H2SO4 c. Cl OCOCH3 CH3CH2Cl AlCl3 g. CH3O COOCH3 Cl2 FeCl3 d. CHO CH3 Br2 FeBr3 h. Br OCH3 SO3 H2SO4

What products are formed when benzene is treated with each alkyl chloride and AlCl3? a. Cl b. Cl c. Cl d. Cl

Draw the products of each reaction. a. CH3 C(CH3)3 KMnO4 d. Br2 FeBr3 b. Br2 h e. NH2NH2 O OH c. Zn(Hg), HCl CH3 C CH2CH2CH3 O f. Br2 OCH2CH3 FeBr3

You have learned two ways to make an alkyl benzene: FriedelCrafts alkylation, and FriedelCrafts acylation followed by reduction. Although some alkyl benzenes can be prepared by both methods, it is often true that only one method can be used to prepare a given alkyl benzene. Which method(s) can be used to prepare each of the following compounds from benzene? Show the steps that would be used. a. b. c. CH2CH3 d. C(CH3)3

Explain why each of the following reactions will not form the given product. Then, design a synthesis of A from benzene and B from phenol (C6H5OH). a. SO3H SO3H COCH3 = A Cl [1] CH3COCl, AlCl3 [2] Cl2, FeCl3 b. OCH3 OCH3 CH3CH2CH2CH2 NO2 = B [1] CH3CH2CH2CH2Cl, AlCl3 [2] HNO3, H2SO4

Rank the compounds in each group in order of increasing reactivity in electrophilic aromatic substitution. a. C6H5NO2, C6H6, C6H5OH d. C6H6, C6H5CH2Cl, C6H5CHCl2 b. C6H6, C6H5Cl, C6H5CHO e. C6H5CH3, C6H5NH2, C6H5CH2NH2 c. C6H6, C6H5NO2, C6H5NH2

Draw all resonance structures for each compound, and explain why a particular substituent has an electron-donating or electron-withdrawing resonance effect: (a) C6H5NO2; (b) C6H5F.

For each of the following substituted benzenes: [1] C6H5Br; [2] C6H5CN; [3] C6H5OCOCH3: a. Does the substituent donate or withdraw electron density by an inductive effect? b. Does the substituent donate or withdraw electron density by a resonance effect? c. On balance, does the substituent make a benzene ring more or less electron rich than benzene itself? d. Does the substituent activate or deactivate the benzene ring in electrophilic aromatic substitution?

Which benzene ring in each compound is more reactive in electrophilic aromatic substitution? a. O O C b. CH3 c. O

For each N-substituted benzene, predict whether the compound reacts faster than, slower than, or at a similar rate to benzene in electrophilic aromatic substitution. Then draw the major product(s) formed when each compound reacts with a general electrophile E+ . a. N b. NH(CH3)2 + c. N(CH3)3 + O2N d. O2N N

Explain each statement in detail using resonance structures. a. A phenyl group (C6H5 ) is an ortho, para director that activates a benzene ring towards electrophilic attack. b. A nitroso group ( NO) is an ortho, para director that deactivates a benzene ring towards electrophilic attack.

Explain why the meta product is formed in the following reaction despite the fact that N(CH3)2 is usually an ortho, para director. NO2 HNO3 H2SO4 N(CH3) N(CH3 2

Draw a stepwise mechanism for each reaction. a. + + Cl AlCl3 HCl b. + + AlCl3 Cl + HCl

Draw a stepwise, detailed mechanism for the following intramolecular reaction. H2SO4 OCH3 OCH3

Draw a stepwise, detailed mechanism for the following reaction. H2SO4 H2O CH3O OH CH3O

FriedelCrafts alkylation of benzene with (2R)-2-chlorobutane and AlCl3 affords sec-butylbenzene. a. How many stereogenic centers are present in the product? b. Would you expect the product to exhibit optical activity? Explain, with reference to the mechanism.

Although two products (A and B) are possible when naphthalene undergoes electrophilic aromatic substitution, only A is formed. Draw resonance structures for the intermediate carbocation to explain why this is observed. E+ naphthalene This product is formed. E + A B This product is not formed. E

Draw a stepwise mechanism for the following reaction, which is used to prepare the pesticide DDT. C CCl3 H DDT O C CCl3 H2SO4 H 2 Cl

Benzene undergoes electrophilic aromatic substitution with anhydrides, compounds having the general structure (RCO)2O, in a reaction that resembles FriedelCrafts acylation. Draw a stepwise mechanism for the reaction of benzene with glutaric anhydride in the presence of AlCl3. [1] AlCl3 [2] H3O CO2H glutaric anhydride + + O O O O

Benzyl bromide (C6H5CH2Br) reacts rapidly with CH3OH to afford benzyl methyl ether (C6H5CH2OCH3). Draw a stepwise mechanism for the reaction, and explain why this 1 alkyl halide reacts rapidly with a weak nucleophile under conditions that favor an SN1 mechanism. Would you expect the para-substituted benzylic halides CH3OC6H4CH2Br and O2NC6H4CH2Br to each be more or less reactive than benzyl bromide in this reaction? Explain your reasoning.

Draw a stepwise mechanism for the following reaction, which is used to prepare bisphenol A (BPA), a widely used monomer in polymer synthesis. Although BPA is not acutely toxic, safety concerns over low-dose exposure, especially in infants, have led to a re-examination of its use in baby bottles and infant formula cans. + O HO HO OH bisphenol A 2 H2SO4 + H2O

Synthesize each compound from benzene and any other organic or inorganic reagents. a. isopropylbenzene b. butylbenzene c. o-butylchlorobenzene d. m-bromonitrobenzene e. o-bromonitrobenzene f. COOH SO3H h. Br COOH j. SO3H CI CI COOH g. COOH NO2 i. Br CH2CH2CH3 NO2 k. CI NO2

Synthesize each compound from benzene and any other organic or inorganic reagents. a. NH2 Br c. NO2 O e. SO3 Na+ g. CI b. NO2 Br CH3 d. NH2 (PABA) sunscreen component HOOC f. NH2 Br

Synthesize each compound from toluene (C6H5CH3) and any other organic or inorganic reagents. a. C6H5CH2Br b. C6H5CH2OH c. C6H5CH2OC(CH3)3 d. C6H5CHO e. COOH Cl f. (CH2) CH3 5CH3 h. HOOC NO2 O2N j. H2N g. C COOH O CH3 i. OH O Br k. CHO Cl O

Devise a synthesis of each compound from phenol (C6H5OH) and any other organic or inorganic reagents. a. CH3O estragole (isolated from basil) b. CH3CH2O OCH3 c. CH3O H2N CH3 NH2

Use the reactions in this chapter along with those learned in Chapters 11 and 12 to synthesize each compound. You may use benzene, acetylene (HC CH), two-carbon alcohols, ethylene oxide, and any inorganic reagents. a. C6H5C CH b. C6H5CH2CH2Br c. C6H5C CCH2CH2OH d. O2N CH2CH2 CHC f. Br OH OH e. g. CI NO2 O

Devise a synthesis of 1-phenyl-1-propyne (C6H5C CCH3) from benzene and organic compounds having 3 Cs. You may use any required inorganic or organic reagents.

Ibufenac, a para-disubstituted arene with the structure HO2CCH2C6H4CH2CH(CH3)2, is a much more potent analgesic than aspirin, but it was never sold commercially because it caused liver toxicity in some clinical trials. Devise a synthesis of ibufenac from benzene and organic halides having fewer than fi ve carbons.

Carboxylic acid X is an intermediate in the multistep synthesis of proparacaine, a local anesthetic. Devise a synthesis of X from phenol and any needed organic or inorganic reagents. several steps O O OH X O2N O O O proparacaine H2N N(CH2CH3)2

Propose a structure of compound C (molecular formula C10H12O) consistent with the following data. C is partly responsible for the odor and fl avor of raspberries. Compound C: IR absorption at 1717 cm1 1H NMR of C 3 H 2 H 2 H ppm 9 0

Compound X (molecular formula C10H12O) was treated with NH2NH2, OH to yield compound Y (molecular formula C10H14). Based on the 1 H NMR spectra of X and Y given below, what are the structures of X and Y? 1 H 1H NMR of X 5 H 6 H 0123456 ppm 78 2 H 5 H multiplet multiplet 1 H 1H NMR of Y 6 H 0123456 ppm

Reaction of p-cresol with two equivalents of 2-methyl-1-propene affords BHT, a preservative with molecular formula C15H24O. BHT gives the following 1 H NMR spectral data: 1.4 (singlet, 18 H), 2.27 (singlet, 3 H), 5.0 (singlet, 1 H), and 7.0 (singlet, 2 H) ppm. What is the structure of BHT? Draw a stepwise mechanism illustrating how it is formed. p-cresol 2-methyl-1-propene (2 equiv) CH3 OH + CH2 BHT (C15H24O) H2SO4 CH3 CH3

Compound Z (molecular formula C9H9ClO) can be converted to the antidepressant bupropion (Figure 18.3) by a series of reactions. Z shows a strong peak in its IR spectrum at 1683 cm1. The 1 H NMR spectrum of Z shows peaks at 1.2 (triplet, 3 H), 2.9 (quartet, 2 H), and 7.28.0 (multiplet, 4 H) ppm. Propose a structure for Z. several Cl CH3 O N C(CH3)3 H Z steps bupropion

The 1 H NMR spectrum of phenol (C6H5OH) shows three absorptions in the aromatic region: 6.70 (2 ortho Hs), 7.14 (2 meta Hs), and 6.80 (1 para H) ppm. Explain why the ortho and para absorptions occur at lower chemical shift than the meta absorption.

Explain the reactivity and orientation effects observed in each heterocycle. E+ E E + E N N N pyridine pyrrole H C3 N H C2 a. Pyridine is less reactive than benzene in electrophilic aromatic substitution and yields 3-substituted products. b. Pyrrole is more reactive than benzene in electrophilic aromatic substitution and yields 2-substituted products

Draw a stepwise, detailed mechanism for the dienonephenol rearrangement, a reaction that forms alkyl-substituted phenols from cyclohexadienes. O H2SO4 OH

Draw a stepwise mechanism for the following intramolecular reaction, which is used in the synthesis of the female sex hormone estrone. Lewis acid or HA several steps OH RO RO HO O A estrone

Although aryl halides are generally inert to nucleophilic substitution, aryl halides that also contain a nitro group ortho or para to the halogen undergo nucleophilic aromatic substitution, as shown in the following example. O2N Cl CH3O O2N OCH3 + Cl + a. Keeping in mind that the reaction cannot follow an SN1 or SN2 mechanism, suggest a mechanism for this process. b. Explain why an electron-withdrawing NO2 group is needed for this nucleophilic substitution to occur. c. Explain why m-chloronitrobenzene does not undergo this reaction.