Organic Chemistry

Janice Gorzynski Smith

Chapter 16

Reactions of Aromatic Compounds - all with Video Answers

Educators

Chapter Questions

Problem 1

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

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 2

In Step [2] of Mechanism 16.1, loss of a proton to form the substitution product was drawn using only one resonance structure. 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.

Henry R

Numerade Educator

Problem 3

Draw a detailed mechanism for the chlorination of benzene using $\mathrm{Cl}_{2}$ and $\mathrm{FeCl}_{3}$.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 4

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 3.24 ).

Nima Gharibi

Numerade Educator

Problem 5

What product is formed when benzene is treated with each organic halide in the presence of $\mathrm{AICl}_{3} ?$
a.
b.
c.

Henry R

Numerade Educator

Problem 6

What acid chloride would be needed to prepare each of the following ketones from benzene using a Friedel-Crafts acylation?
a.
b.
c.

Henry R

Numerade Educator

Problem 7

What acylium ion is formed from each acid chloride?
a.
b.
c.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 8

Which halides are unreactive in a Friedel-Crafts alkylation reaction?
a.
b.
c.
d.

Shalini Tyagi

Numerade Educator

Problem 9

Draw a stepwise mechanism for the following reaction.

Colton K

Numerade Educator

Problem 10

Draw the product of each reaction.
a.
b.
c.
d.

Shalini Tyagi

Numerade Educator

Problem 11

Draw a stepwise mechanism for the intramolecular Friedel-Crafts acylation of compound A to form B. B can be converted in one step to the antidepressant sertraline.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 12

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

Madi Sousa

Numerade Educator

Problem 13

(a) Draw resonance structures for the carbocation formed after loss of a leaving group from phytyl diphosphate. (b) Draw the two-step mechanism for Friedel-Crafts alkylation of 1,2 -dihydroxynaphthoic acid with this carbocation to form $\mathrm{X}$.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 14

Which substituents have an electron-withdrawing and which have an electron-donating
inductive effect:
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2}-;$
(b) $\mathrm{Br}-$
(c) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{O}-?$

Nima Gharibi

Numerade Educator

Problem 15

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.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 16

Classify each substituent as electron donating or electron withdrawing.
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 17

Draw the products formed when each compound is treated with $\mathrm{HNO}_{3}$ and $\mathrm{H}_{2} \mathrm{SO}_{4}$. State whether the reaction occurs faster or slower than a similar reaction with benzene.
a.
b.
c.
d.
e.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 18

Determine which ring in each compound is more reactive toward electrophiles, and explain your choice.
a.
b.

Shalini Tyagi

Numerade Educator

Problem 19

Consider the tetracyclic compound with rings labeled $A-D .$ (a) Which ring is the most reactive in electrophilic aromatic substitution? (b) Which ring is the least reactive in electrophilic aromatic substitution?

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 20

Label each compound as more or less reactive than benzene in electrophilic aromatic substitution.
a.
b.
c.
d.

Shalini Tyagi

Numerade Educator

Problem 21

Rank the following compounds in order of increasing reactivity in electrophilic aromatic substitution.

Nima Gharibi

Numerade Educator

Problem 22

Draw all resonance structures for the carbocation formed by ortho attack of the electrophile ${ }^{+} \mathrm{NO}_{2}$ on each starting material. Label any resonance structures that are especially stable or unstable.
a.
b.
c.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 23

Draw the products of each reaction.
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 24

Which of the following compounds undergo Friedel-Crafts alkylation with $\mathrm{CH}_{3} \mathrm{Cl}$ and $\mathrm{AICl}_{3}$ ? Draw the products formed when a reaction occurs.
a.
b.
c.
d.

Shalini Tyagi

Numerade Educator

Problem 25

Draw the products formed when each compound is treated with $\mathrm{HNO}_{3}$ and $\mathrm{H}_{2} \mathrm{SO}_{4}$.
a.
b.
c.
d.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 26

Devise a synthesis of each compound from the indicated starting material.
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 27

Draw the products of each reaction.
a.
b.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 28

Draw a stepwise mechanism for the following reaction that forms ether D. D can be converted to the antidepressant fluoxetine (trade name Prozac) in a single step.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 29

Draw the products of each reaction.
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 30

Draw all products formed when $m$ -chlorotoluene is treated with $\mathrm{KNH}_{2}$ in $\mathrm{NH}_{3}$.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 31

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

Shalini Tyagi

Numerade Educator

Problem 32

Write out the two-step sequence that converts benzene to each compound.
a.
b.

Shalini Tyagi

Numerade Educator

Problem 33

What steps are needed to convert benzene to $p$ -isobutylacetophenone, a synthetic intermediate used in the synthesis of the anti-inflammatory agent ibuprofen.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 34

Synthesize each compound from benzene.
a.
b.
c.
d.
e.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 35

Synthesize each compound from benzene.
a.
b.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 36

Synthesize each compound from benzene.
a.
b.
c.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 37

Draw the products formed when $A$ and $B$ are treated with each of the following reagents: (a) $\mathrm{Br}_{2}, \mathrm{FeBr}_{3} ;$ (b) $\mathrm{HNO}_{3}, \mathrm{H}_{2} \mathrm{SO}_{4} ;$ (c) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{COCl}$, $\mathrm{AICl}_{3}$

Shalini Tyagi

Numerade Educator

Problem 38

What is the major product formed by an intramolecular Friedel-Crafts acylation of the following compound?

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 39

Draw the products formed when phenol $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{OH}\right)$ is treated with each set of reagents.
a. $[1] \mathrm{HNO}_{3}, \mathrm{H}_{2} \mathrm{SO}_{4} ;[2] \mathrm{Sn}, \mathrm{HCl}$
b. $[1]\left(\mathrm{CH}_{3} \mathrm{CH}_{2}\right)_{2} \mathrm{CHCOCl}, \mathrm{AICl}_{3} ;[2] \mathrm{Zn}(\mathrm{Hg}), \mathrm{HCl}$
c. $[1] \mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{Cl}, \mathrm{AlCl}_{3} ;[2] \mathrm{Br}_{2}, h v$
d. $[1]\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CHCl}, \mathrm{AICl}_{3} ;[2] \mathrm{KMnO}_{4}$

Shalini Tyagi

Numerade Educator

Problem 40

Draw the products formed when each compound is treated with $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{COCl}, \mathrm{AICl}_{3}$
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 41

Draw the products of each reaction.
a.
b.
c.
d.
e.
f.

Shalini Tyagi

Numerade Educator

Problem 42

What products are formed when benzene is treated with each alkyl chloride and $\mathrm{AICl}_{3}$ ?
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 43

Draw the products of each reaction.
a.
b.
c.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 44

You have learned two ways to make an alkyl benzene: Friedel-Crafts alkylation, and Friedel-Crafts 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.

Shalini Tyagi

Numerade Educator

Problem 45

Identify $\mathrm{X}$ and $\mathrm{Y},$ the products of key steps in two syntheses of pioglitazone, a drug used to treat diabetes.
a.
b.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 46

Identify $\mathrm{M}$ and $\mathrm{N}$ in the following reaction sequence, two steps in the original synthesis of the non-sedating antihistamine fexofenadine

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 47

Draw the structure of $\mathrm{A},$ an intermediate in the synthesis of the antipsychotic drug risperidone. Explain why three rings in risperidone are considered aromatic.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 48

D is an intermediate in the synthesis of rosiglitazone (trade name Avandia), a drug used to treat type 2 diabetes. Suggest two different methods to prepare the ether in D by substitution reactions.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 49

Rank the compounds in each group in order of increasing reactivity in electrophilic aromatic substitution:
(a) $\mathrm{C}_{6} \mathrm{H}_{6}, \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{Cl}, \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CHO}$
$\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{OCH}_{3} ;$ (b) $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{3}, \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NH}_{2}, \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NH}_{2}, \mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CONH}_{2}$

Shalini Tyagi

Numerade Educator

Problem 50

For each of the following substituted benzenes: [1] $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{Br} ;$ [2] $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CN}$
[3] $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{OCOCH}_{3}$
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?
On balance, does the substituent make a benzene ring more or less
c. electron rich than benzene itself?
d. Does the substituent activate or deactivate the benzene ring in electrophilic aromatic substitution?

Nima Gharibi

Numerade Educator

Problem 51

Determine which ring in each compound is more reactive in electrophilic aromatic substitution, and draw the product(s) formed when each compound is treated with the general electrophile $\mathrm{E}^{+}$.
a.
b.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 52

Consider the tetracyclic aromatic compound drawn below, with rings labeled as $\mathrm{A}, \mathrm{B}, \mathrm{C},$ and $\mathrm{D} .$ (a) Which of the four rings is most reactive in electrophilic aromatic substitution? (b) Which of the four rings is least reactive in electrophilic aromatic substitution? (c) What are the major product(s) formed when this compound is treated with one equivalent of $\mathrm{Br}_{2} ?$

Shalini Tyagi

Numerade Educator

Problem 53

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 $\mathrm{E}^{+}$.
a.
b.
c.
d.

Shalini Tyagi

Numerade Educator

Problem 54

What is the major product of electrophilic addition of HBr to the following alkene? Explain your choice.

Shalini Tyagi

Numerade Educator

Problem 55

Using resonance structures, explain why a nitroso group (-NO) is an ortho, para director that deactivates a benzene ring toward electrophilic attack.

Shalini Tyagi

Numerade Educator

Problem 56

Explain this observation: Ethyl 3-phenylpropanoate $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CO}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}\right)$ reacts with electrophiles to afford ortho- and
para-disubstituted arenes, but ethyl 3 -phenylprop-2-enoate $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}=\mathrm{CHCO}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}\right)$ reacts with electrophiles to afford meta-
disubstituted arenes.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 57

Rank the aryl halides in each group in order of increasing reactivity in nucleophilic aromatic substitution by an addition-elimination mechanism.
a. chlorobenzene, $p$ -fluoronitrobenzene, $m$ -fluoronitrobenzene
b. 1-fluoro-2,4-dinitrobenzene, 1-fluoro-3,5-dinitrobenzene, 1-fluoro-3,4-
dinitrobenzene
c. 1-fluoro-2,4-dinitrobenzene, 4-chloro-3-nitrotoluene, 4-fluoro-3-
nitrotoluene

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 58

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

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 59

Draw a stepwise, detailed mechanism for the following reaction.

Ian Kaigh

Numerade Educator

Problem 60

Draw a stepwise mechanism for the following reaction, which involves two Friedel-Crafts reactions. B was an intermediate in the synthesis of the antidepressant sertraline (Problem 16.11 ).

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 61

Friedel-Crafts alkylation of benzene with $(R)-2$ -chlorobutane and $\mathrm{AICl}_{3}$ 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.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 62

Fluorination of a benzene ring can be accomplished with Selectfluor, a reagent that contains a fluorine bonded to a positively charged nitrogen atom. Fluorination is a useful reaction because several common drugs, such as the cholesterol-lowering drug atorvastatin, contain a fluorine bonded to an aromatic ring. Assuming that fluorination is analogous to other examples of electrophilic aromatic substitution, draw a stepwise mechanism for the following reaction.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 63

Draw a stepwise mechanism for the following substitution. Explain why 2-chloropyridine reacts faster than chlorobenzene in this type of reaction.

Nima Gharibi

Numerade Educator

Problem 64

Although two products (A and B) are possible when naphthalene undergoes electrophilic aromatic substitution, only $\mathrm{A}$ is formed. Draw resonance structures for the intermediate carbocation to explain why this is observed.

Nima Gharibi

Numerade Educator

Problem 65

Draw a stepwise mechanism for the following reaction, which results in the synthesis of bisphenol $\mathrm{F}(\mathrm{R}=\mathrm{H}),$ an additive used in a variety of packaging materials. Bisphenol $\mathrm{F}$ is related to BPA (bisphenol $\mathrm{A}, \mathrm{R}=$ $\mathrm{CH}_{3}$ ), a reagent used to harden some plastics, now removed from certain baby products because of its estrogen-like activity that can disrupt endocrine pathways.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 66

Benzyl bromide $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{Br}\right)$ reacts rapidly with $\mathrm{CH}_{3} \mathrm{OH}$ to afford benzyl methyl ether $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{OCH}_{3}\right) .$ Draw a stepwise mechanism for the reaction, and explain why this $1^{\circ}$ alkyl halide reacts rapidly with a weak nucleophile under conditions that favor an $\mathrm{S}_{\mathrm{N}} 1$ mechanism. Would you expect the para-substituted benzylic halides $\mathrm{CH}_{3} \mathrm{OC}_{6} \mathrm{H}_{4} \mathrm{CH}_{2} \mathrm{Br}$ and $\mathrm{O}_{2} \mathrm{NC}_{6} \mathrm{H}_{4} \mathrm{CH}_{2} \mathrm{Br}$ to each be more or less reactive than benzyl bromide in this reaction? Explain your reasoning.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 67

Synthesize each compound from benzene, organic halides with $<5 \mathrm{C}^{\prime} \mathrm{s}$ and any other organic or inorganic reagents.
a.
b.
c.
d.
e.
f.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 68

Synthesize each compound from toluene $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{3}\right)$ and any other organic or inorganic reagents.
a.
b.
c.

Shalini Tyagi

Numerade Educator

Problem 69

Use the reactions in this chapter along with those learned in Chapters 11 and 12 to synthesize each compound. You may use benzene, acetylene $(\mathrm{HC} \equiv \mathrm{CH}),$ ethanol, ethylene oxide, and any inorganic reagents.
a.
b.
c.
d.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 70

$\mathrm{HO}_{2} \mathrm{CCH}_{2} \mathrm{C}_{6} \mathrm{H}_{4} \mathrm{CH}_{2} \mathrm{CH}\left(\mathrm{CH}_{3}\right)_{2},$ 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 five carbons.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 71

Carboxylic acid $\mathrm{X}$ is an intermediate in the multistep synthesis of proparacaine, a local anesthetic. Devise a synthesis of $\mathrm{X}$ from phenol and any needed organic or inorganic reagents.

Nima Gharibi

Numerade Educator

Problem 72

Identify the structures of isomers $A$ and $B$ (molecular formula $C_{8} H g B r$ ).

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 73

Propose a structure of compound $\mathrm{C}$ (molecular formula $\left.\mathrm{C}_{10} \mathrm{H}_{12} \mathrm{O}\right)$ consistent with the following data. $\mathrm{C}$ is partly responsible for the odor and flavor of raspberries. Compound C: IR absorption at $1717 \mathrm{~cm}^{-1}$.

Nima Gharibi

Numerade Educator

Problem 74

Compound $X$ (molecular formula $C_{10} H_{12}$ O) was treated with $N H_{2} N H_{2}$, "OH to yield compound Y (molecular formula $\mathrm{C}_{10} \mathrm{H}_{14}$ ). Based on the ${ }^{1} \mathrm{H}$ NMR spectra of $\mathrm{X}$ and $\mathrm{Y}$ given below, what are the structures of $\mathrm{X}$ and $\mathrm{Y} ?$

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 75

Reaction of $p$ -cresol with two equivalents of 2 -methylprop-1-ene affords BHT, a preservative with molecular formula $\mathrm{C}_{15} \mathrm{H}_{24} \mathrm{O}$. BHT gives the following ${ }^{1} \mathrm{H}$ NMR spectral data: 1.4 (singlet, $18 \mathrm{H}$ ), 2.27 (singlet, $3 \mathrm{H}$ ), 5.0 (singlet, $1 \mathrm{H}$ ), and 7.0 (singlet, $2 \mathrm{H}$ ) ppm. What is the structure of BHT? Draw a stepwise mechanism illustrating how it is formed.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 76

Devise a synthesis of optically active (S)-fluoxetine (trade name Prozac) from the given starting materials and any other needed reagents.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 77

The ${ }^{1} \mathrm{H}$ NMR spectrum of phenol $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{OH}\right)$ shows three absorptions in the aromatic region: 6.70 (2 ortho H's), 7.14 ( 2 meta H's), and 6.80 ( 1 para H) ppm. Explain why the ortho and para absorptions occur at lower chemical shift than the meta absorption.

George Bennett

Numerade Educator

Problem 78

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

Nima Gharibi

Numerade Educator

Problem 79

Draw a stepwise mechanism for the dienone-phenol rearrangement, a reaction that forms alkyl-substituted phenols from cyclohexadienones.

George Bennett

Numerade Educator

Problem 80

Draw a stepwise mechanism for the following intramolecular reaction, which is used in the synthesis of the female sex hormone estrone.

Nima Gharibi

Numerade Educator

Problem 81

The bicyclic heterocycles quinoline and indole undergo electrophilic aromatic substitution to give the products shown.
(a) Explain why electrophilic substitution occurs on the ring without the N atom for quinoline, but occurs on the ring with the $\mathrm{N}$ atom in indole. (b) Explain why electrophilic substitution occurs more readily at $\mathrm{C} 8$ than $\mathrm{C} 7$ in quinoline. (c) Explain why electrophilic substitution occurs more readily at $\mathrm{C} 3$ rather than $\mathrm{C} 2$ of indole.

George Bennett

Numerade Educator

Problem 82

Devise a stepwise mechanism for the following reaction. The reaction does not take place by direct electrophilic aromatic substitution at C2. (Hint: The mechanism begins with addition of an electrophile at C3.)

Nima Gharibi

Numerade Educator