Organic Chemistry

Paula Yurkanis Bruice

Chapter 17

Reactions at the $\alpha$ -Carbon - all with Video Answers

Educators

Chapter Questions

Problem 1

Explain why the $\mathrm{p} K_{\mathrm{a}}$ of a hydrogen bonded to the $s p^{3}$ carbon of propene is greater $\left(\mathrm{p} K_{\mathrm{a}}=42\right)$ than that of any of the carbon acids listed in Table $17.1,$ but is less than the $\mathrm{p} K_{\mathrm{a}}$ of an alkane $\left(\mathrm{p} K_{\mathrm{a}}>60\right)$

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Problem 2

Give an example for each of the following: a. a $\beta$ -keto nitrile b. a $\beta$ -diester c. a $\beta$ -keto aldehyde

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Problem 3

Explain why a base can remove a proton from the $\alpha$ -carbon of $N, N$ -dimethylethanamide but not from the $\alpha$ -carbon of either $N$ -methylethanamide or ethanamide.

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Problem 4

Explain why the $\alpha$ -hydrogen of an $N, N$ -disubstituted amide is less acidic $\left(\mathrm{p} K_{\mathrm{a}}=30\right)$ than the $\alpha$ -hydrogen
of an ester $\left(\mathrm{p} K_{\mathrm{a}}=25\right)$

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Problem 5

Rank the compounds in each of the following groups from strongest acid to weakest acid:

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Problem 6

Explain why $92 \%$ of 2,4 -pentanedione exists as the enol tautomer in hexane but only $15 \%$ of this compound exists as the enol tautomer in water.

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Problem 7

Draw the enol tautomers for each of the following compounds. For compounds that have more than one enol tautomer, indicate the one that is more stable.

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Problem 8

When a dilute solution of acetaldehyde in $\mathrm{D}_{2} \mathrm{O}$ containing $\mathrm{NaOD}$ is shaken, explain why the methyl hydrogens are exchanged with deuterium but the hydrogen attached to the carbonyl carbon is not.

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Problem 9

Explain why a racemic mixture is formed when ( $R$ )-2-methylpentanal is dissolved in an acidic or basic solution.

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Problem 10

A ketone undergoes acid-catalyzed bromination, acid-catalyzed chlorination, racemization, (sce page 408) and acid-catalyzed deuterium exchange at the $\alpha$ -carbon. All of these reactions have similar rate constants. What does this tell you about the mechanisms of these reactions?

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Problem 11

Show how the following compounds can be prepared from the given starting material:

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Problem 12

What compound is formed when a dilute solution of cyclohexanone is shaken with $\mathrm{NaOD}$ in $\mathrm{D}_{2} \mathrm{O}$ for several hours?

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Problem 13

Explain why alkylation of an $\alpha$ -carbon works best if the alkyl halide used in the reaction is a primary alkyl halide, and why alkylation does not work at all if a tertiary alkyl halide is used.

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Problem 14

How could each of the following compounds be prepared from a ketone and an organohalide?

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Problem 15

How many stereoisomers are obtained from each of the syntheses described in Problem $14 ?$

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Problem 16

How could each of the following compounds be prepared from cyclohexanone?

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Problem 17

Describe how the following compounds could be prepared from cyclohexanone using an enamine intermediate:

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Problem 18

Draw the products of the following reactions:

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Problem 19

What reagents should be used to prepare the following compounds?

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Problem 20

What aldol addition product is formed from each of the following compounds?

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Problem 21

What aldehyde or ketone would be obtained when each of the following compounds is heated in a basic aqueous solution?

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Problem 22

What product is obtained from the aldol condensation of cyclohexanone?

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Problem 23

How could you prepare the following compound using a starting material that contains no more than three carbons?

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Problem 24

How could you prepare the following compound using a starting material that contains no more than three carbons?

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Problem 25

Describe how the following compounds can be prepared using an aldol addition in the first step of the synthesis:

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Problem 26

What two carbonyl compounds are required for the synthesis of morachalcone A (the aromatase inhibitor discussed in the box below), via a Claisen-Schmidt condensation?

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Problem 27

What two carbonyl compounds are required for the synthesis of morachalcone A (the aromatase inhibitor discussed in the box below), via a Claisen-Schmidt condensation?

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Problem 28

Draw the products of the following reactions:

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Problem 29

Which of the following esters cannot undergo a Claisen condensation?

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Problem 30

What is the product of each of the following reactions?

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Problem 31

Show how each of the following compounds can be prepared from methyl phenyl ketone:

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Problem 32

Write the mechanism for the reaction of a 1.7 -diester with an alkoxide ion to form a cyclic $\beta$ -keto ester.

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Problem 33

If the preference for formation of a six-membered ring were not so great, what other cyclic product would be formed from the intramolecular aldol addition of a. 2,6 -heptanedione?
b. 2,8 -nonanedione?

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Problem 34

Can 2,4 -pentanedione undergo an intramolecular aldol addition? If so, why? If not, why not?

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Problem 35

Draw the product of the reaction of each of the following compounds with a base:

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Problem 36

Draw the product obtained by heating each pair of ketones in a basic solution.

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Problem 37

What two carbonyl compounds are needed to synthesize each of the following compounds, using a Robinson annulation?

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Problem 38

Which of the following compounds will decarboxylate when heated?

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Problem 39

What alkyl bromide(s) should be used in the malonic ester synthesis of each of the following carboxylic acids? a. propanoic acid
c. 3-phenylpropanoic acid
b. 2-methylpropanoic acid
d. 4-methylpentanoic acid

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Problem 40

Explain why the following carboxylic acids cannot be prepared by a malonic ester synthesis:

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Problem 41

What alkyl bromide should be used in the acetoacetic ester synthesis of each of the following methyl ketones? tanone
b. 2-octanone
c. 4-phenyl-2-butanone

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Problem 42

Starting with methyl propanoate, how could you prepare 4-methyl-3-heptanone?

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Problem 43

Design a synthesis for each of the following compounds using the given starting material:

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Problem 44

Propose a mechanism for the formation of fructose-1,6-bisphosphate from dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, using hydroxide ion as the catalyst.

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Problem 45

Palmitic acid is a straight-chain saturated 16 -carbon fatty acid. How many moles of malonyl-CoA are required for the synthesis of one mole of palmitic acid?

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Problem 46

a. If the biosynthesis of palmitic acid were carried out with $\mathrm{CD}_{3}$ COSR and nondeuterated malonyl thioester, how many deuterium atoms would be incorporated into palmitic acid? b. If the biosynthesis of palmitic acid were carried out with $$\mathrm{OOCCD}_{2} \mathrm{COSR}$$ and nondeuterated acetyl thioester, how many deuterium atoms would be incorporated into palmitic acid?

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Problem 47

When the enzymatic decarboxylation of acetoacetate is carried out in $$\mathrm{H}_{2}^{18} \mathrm{O}$$, all the acetone that is formed contains $^{18} \mathrm{O}$ What does this tell you about the mechanism of the reaction?

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Problem 48

Draw a structure for each of the following:
a. ethyl acctoacetate
b. $\alpha$ -methylmalonic acid
c. a $\beta$ -keto ester
d. the enol tautomer of cyclopentanone
e. the carboxylic acid obtained from the malonic ester synthesis when the alkyl halide is propyl bromide

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Problem 49

Draw the products of the following reactions:
a. diethyl heptanedioate: (1) sodium ethoxide; (2) HCl
b. pentanoic acid $+\mathrm{PBr}_{3}+\mathrm{Br}_{2},$ followed by hydrolysis
c. acetone + LDA/THF: (1) slow addition of ethyl acetate; (2) HCl
d. diethyl 2-ethylhexanedioate: (1) sodium ethoxide; (2) HCl
e. diethyl malonate: (1) sodium ethoxide; (2) isobutyl bromide; $$\text { (3) } \mathrm{HCl}, \mathrm{H}_{2} \mathrm{O}+\Delta$$
f. acetophenone + LDA/THF: (1) slow addition of diethyl carbonate: (2) HCl

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Problem 50

Number the following compounds in order of increasing $\mathrm{p} K_{\mathrm{a}}$ value.

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Problem 51

The $^{1} \mathrm{H}$ NMR chemical shifts of nitromethane, dinitromethane, and trinitromethane are at $\delta 6.10, \delta 4.33,$ and $\delta 7.52 .$ Match each chemical shift with the compound. Explain how chemical shift correlates with $\mathrm{p} K_{\mathrm{a}}$

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Problem 52

Which of the following compounds decarboxylates when heated?

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Problem 53

Draw the products of the following reactions: a. 1,3 -cyclohexanedione $+$ LDA/THF, followed by allyl bromide
b. $\gamma$ -butyrolactone $+$ LDA/THF, followed by methyl iodide
c. 2,7 -octanedione $+$ sodium hydroxide
d. diethyl 1,2-benzenedicarboxylate + sodium ethoxide: (1) slow addition of ethyl acetate; (2) HCl

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Problem 54

A racemic mixture of 2-methyl-1-phenyl-1-butanone is formed when ( $R$ )-2-methyl-1-phenyl-1-butanone is dissolved in an acidic or basic aqueous solution. Give an example of another ketone that undergoes acid- or base-catalyzed racemization.

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Problem 55

Draw the products of the following reactions:

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Problem 56

What is the product of the following reaction?

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Problem 57

An aldol addition can be catalyzed by acids as well as by bases. Propose a mechanism for the acid-catalyzed aldol addition of propanal.

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Problem 58

In the presence of excess base and excess halogen, a methyl ketone is converted to a carboxylate ion. The reaction is known as the haloform reaction cause one of the products is haloform (chloroform, bromoform, or iodoform). Before spectroscopy became a routine analytical tool, the haloform reaction, served as a test for methyl ketones: the formation of iodoform, a bright yellow compound, signaled that a methyl ketone was present. Why do only methyl ketones form a haloform?

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Problem 59

Identify A-L.

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Problem 60

Using cyclopentanone as the reactant, show the product of a. acid-catalyzed keto-enol interconversion. b. an aldol addition.
c. an aldol condensation.

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Problem 61

Show how 4 -methyl- 3 -hexanol can be synthesized from 3 -pentanone.

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Problem 62

Show how the following compound can be synthesized from the given starting material.

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Problem 63

Show how the following compounds can be prepared from cyclohexanone:

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Problem 64

A $\beta, \gamma$ -unsaturated carbonyl compound rearranges to a more stable conjugated $\alpha, \beta$ -unsaturated compound in the presence of either acid or base. a. Propose a mechanism for the base-catalyzed rearrangement. b. Propose a mechanism for the acid-catalyzed rearrangement.

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Problem 65

There are other condensation reactions similar to the aldol and Claisen condensations: a. The Perkin condensation is the condensation of an aromatic aldehyde and acetic anhydride. Draw the product obtained from the following Perkin condensation:
b. What compound is formed if water is added to the product of a Perkin condensation? c. The Knoevenagel condensation is the condensation of an aldehyde or a ketone that has no $\alpha$ -hydrogens and a compound such as diethyl malonate that has an $\alpha$ -carbon flanked by two electron-withdrawing groups. Draw the product obtained from the following Knoevenagel condensation:

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Problem 66

Indicate how each of the following compounds can be synthesized from the given starting material and any other necessary reagents:

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Problem 67

The Reformatsky reaction is an addition reaction in which an organozinc reagent is used instead of a Grignard reagent to add to the carbonyl group of an aldehyde or a ketone. Because the organozinc reagent is less reactive than a Grignard reagent, a nucleophilic addition to the ester group does not occur. The organozinc reagent is prepared by treating an $\alpha$ -bromo ester with zinc. Describe how each of the following compounds can be prepared, using a Reformatsky reaction:

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Problem 68

The ketone whose $1 \mathrm{H}$ NMR spectrum is shown here was obtained as the product of an acctoacctic ester synthesis. What alkyl halide was used in the synthesis?

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Problem 69

Indicate how the following compounds can be synthesized from cyclohexanone and any other necessary reagents:

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Problem 70

Compound A with molecular formula $\mathrm{C}_{6} \mathrm{H}_{10}$ has two peaks in its $^{1} \mathrm{H}$ NMR spectrum, both of which are singlets (with ratio 9: 1 ). Compound $\mathbf{A}$ reacts with an acidic aqueous solution containing mercuric sulfate to form compound $\mathbf{B}$, which gives a positive iodoform test (Problem 58 ) and has an $^{1} \mathrm{H}$ NMR spectrum that shows two singlets (with ratio 3: 1 ). Identify $\mathbf{A}$ and $\mathbf{B}$.

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Problem 71

a. What carboxylic acid is formed when the malonic ester synthesis is carried out with one equivalent of malonic ester, one equivalent of . 5 -dibromopentane, and two equivalents of base?
b. What carboxylic acid is formed when the malonic ester synthesis is carried out with two equivalents of malonic ester, one equivalent of
1.5-dibromopentane, and two equivalents of base?

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Problem 72

Draw the products of the following reactions:

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Problem 73

Show how the following compound can be prepared from starting materials that have no more than five carbons:

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Problem 74

a. Show how the amino acid alanine can be synthesized from propanoic acid. (The structures of the amino acids can be found on page $987 .)$
b. Show how the amino acid glycine can be synthesized from phthalimide and diethyl 2-bromomalonate.

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Problem 75

Show how the following compounds can be synthesized. The only carbon-containing compounds available to you for each synthesis are shown.

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Problem 76

A student tried to prepare the following compounds using aldol condensations. Which of these compounds was she successful in synthesizing? Explain why the other syntheses were not successful.

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Problem 77

Explain why the following bromoketone forms different bicyclic compounds under different reaction conditions:

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Problem 78

A Mannich reaction puts a $$\mathrm{NCH}_{2}$$ group on the $\alpha$ -carbon of a carbon acid. Propose a mechanism for the reaction.

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Problem 79

A carboxylic acid is formed when an $\alpha$ -haloketone reacts with hydroxide ion. This reaction is called a Favorskii reaction. Propose a mechanism for the following Favorskii reaction.

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Problem 80

An $\alpha, \beta$ -unsaturated carbonyl compound can be prepared by a reaction known as selenenylation-oxidation reaction. A selenoxide is formed as an intermediate. Propose a mechanism for the reaction.

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Problem 81

What carbonyl compounds are required to prepare a compound with molecular formula $$\mathrm{C}_{10} \mathrm{H}_{10} \mathrm{O} \text { whose }^{1} \mathrm{H} \mathrm{NMR}$$ spectrum is shown below?

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Problem 82

Ninhydrin reacts with an amino acid to form a purple-colored compound. Propose a mechanism to account for the formation of the colored compound.

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Problem 83

A Cannizzaro reaction is the reaction of an aldehyde that has no $\alpha$ -hydrogens with concentrated aqueous sodium hydroxide. In this reaction, half the aldehyde is converted to a carboxylic acid and the other half is converted to an alcohol. Propose a mechanism for the following Cannizzaro reaction:

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Problem 84

Propose a mechanism for each of the following reactions:

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Problem 85

The following reaction is known as the benzoin condensation. The reaction does not take place if sodium hydroxide is used instead of sodium cyanide. Propose a mechanism for the reaction and explain why the reaction does not occur if hydroxide ion is the base.

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Problem 86

Orsellinic acid, a common constituent of lichens, is synthesized from the condensation of acetyl thioester and malonyl thioester. If a lichen is grown on a Propose a mechanism for the reaction and explain why the reaction does not occur if hydroxide ion is the base.

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Problem 87

Alkylation of the following compound with methyl iodide under two different conditions forms two different ketoesters (A and $\mathbf{B}$ ). Each ketoester forms a cyclic diketone ( $\mathbf{C}$ and $\mathbf{D}$ ) when treated with methoxide ion in methanol. a. Draw the structures of $\mathbf{A}$ and $\mathbf{B}$, and indicate the conditions used in the alkylation reaction that cause that ketoester to be formed.
b. Draw the mechanism for the conversion of A to C.

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Problem 88

Propose a mechanism for the following reaction.

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Problem 89

A compound known as Hagemann's ester can be prepared by treating a mixture of formaldehyde and ethyl acetoacetate first with base and then with acid and heat. Write the structure for the product of each of the steps. a. The first step is an aldol-like condensation.
b. The second step is a Michael addition.
c. The third step is an intramolecular aldol addition.
d. The final transformation includes a dehydration and a hydrolysis followed by a decarboxylation.

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Problem 90

Amobarbital is a sedative marketed under the trade name Amytal. Propose a synthesis of amobarbital, using diethyl malonate and urea (page 2) as two of the starting materials.

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Problem 91

Propose a mechanism for the following reaction:

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