Organic Chemistry

John McMurry

Chapter 22

Carbonyl Alpha-Substitution Reactions - all with Video Answers

Educators

Chapter Questions

Problem 1

Draw structures for the enol tautomers of the following compounds:
(a) Cyclopentanone $\quad$ (b) Methyl thioacetate $\quad$ (c) Ethyl acetate (d) Propanal
(e) Acetic acid (f) Phenylacetone

Ronald Prasad

Ronald Prasad

Numerade Educator

Problem 2

How many acidic hydrogens does each of the molecules listed in Problem 22.1 have? Identify them.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 3

Draw structures for all monoenol forms of the following molecule. Which would you expect to be most stable? Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 4

Write the complete mechanism of the deuteration of acetone on treatment with $D_{3} O^{+}$.
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 5

Show how you might prepare 1 -penten-3-one from 3 -pentanone.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 6

If methanol rather than water is added at the end of a Hell-Volhard-zelinskil reaction, an ester rather than an acid is produced. Show how you could carry out the following transformation, and propose a mechanism for the ester-forming step.
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 7

Identify the most acidic hydrogens in each of the following molecules:
$\begin{array}{ll}\text { (a) } \mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CHO} & \text { (b) }\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCOCH}_{3}\end{array}$
(c) $\mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H}$
(d) Benzamide
(e) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CN}$
(f) $\mathrm{CH}_{3} \mathrm{CON}\left(\mathrm{CH}_{3}\right)_{2}$

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 8

Draw a resonance structure of the acetonitrile anion, $^{-}: C H_{2} C=N,$ and account for the acidity of nitriles.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 9

Why do you suppose ketone halogenations in acidic media are referred to as being acidcatalyzed, whereas halogenations in basic media are base-promoted? In other words, why is a full equivalent of base required for halogenation?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 10

How could you use a malonic ester synthesis to prepare the following compounds? Show all steps.
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 11

Monoalkylated and dialkylated acetic acids can be prepared by the malonic ester synthesis, but trialkylated acetic acids (R $_{3} \mathrm{CCO}_{2} \mathrm{H}$ ) can't be prepared. Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 12

How could you use a malonic ester synthesis to prepare the following compound?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 13

What alkyl halides would you use to prepare the following ketones by an acetoacetic ester synthesis?
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 14

Which of the following compounds cannot be prepared by an acetoacetic ester synthesis? Explain.
(a) Phenylacetone $\quad$ (b) Acetophenone (c) 3,3 -Dimethyl-2-butanone

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 15

How would you prepare the following compound using an acetoacetic ester synthesis?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 16

Show how you might prepare the following compounds using an alkylation reaction as the key step:
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 17

Show the steps in preparing each of the following substances using either a malonic ester synthesis or an acetoacetic ester synthesis:
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 18

Unlike most $\beta$ -diketones, the following $\beta$ -diketone has no detectable enol content and is about as acidic as acetone. Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 19

For a given $\alpha$ hydrogen atom to be acidic, the $\mathrm{C}-\mathrm{H}$ bond must be parallel to the $p$ orbitals of the $\mathrm{C}=\mathrm{O}$ double bond (that is, perpendicular to the plane of the adjacent carbonyl group). Identify the most acidic hydrogen atom in the conformation shown for the following structure. Is it axial or equatorial?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 20

Identify all the acidic hydrogens $\left(p K_{a}<25\right)$ in the following molecules:
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 21

Rank the following compounds in order of increasing acidity:
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 22

Write resonance structures for the following anions:
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 23

Base treatment of the following $\alpha, \beta$ -unsaturated carbonyl compound yields an anion by removal of $\mathrm{H}^{+}$ from the $\gamma$ carbon. Why are hydrogens on the $\gamma$ carbon atom acidic?
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 24

Treatment of 1-phenyl-2-propenone with a strong base such as LDA does not yield an anion, even though it contains a hydrogen on the carbon atom next to the carbonyl group. Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 25

Predict the product(s) of the following reactions:
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 26

Which, if any, of the following compounds can be prepared by a malonic ester synthesis? Show the alkyl halide you would use in each case.
(a) Ethyl pentanoate
(b) Ethyl 3-methylbutanoate
(c) Ethyl 2-methylbutanoate
(d) Ethyl 2,2 -dimethylpropanoate

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 27

Which, if any, of the following compounds can be prepared by an acetoacetic ester synthesis? Explain.
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 28

How would you prepare the following ketones using an acetoacetic ester synthesis?
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 29

How would you prepare the following compounds using either an acetoacetic ester synthesis or a malonic ester synthesis?
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 30

Which of the following substances would undergo the haloform reaction?
(a) $\mathrm{CH}_{3} \mathrm{COCH}_{3}$
(b) Acetophenone $\quad(\mathrm{c}) \mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CHO}$$$\text { (d) } \mathrm{CH}_{3} \mathrm{CO}_{2} \mathrm{H} \quad \text { (e) } \mathrm{CH}_{3} \mathrm{C}=\mathrm{N}$$

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 31

How might you convert geraniol into either ethyl geranylacetate or geranylacetone?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 32

Aprobarbital, a barbiturate once used in treating insomnia, is synthesized in three steps from diethyl malonate. Show how you would synthesize the necessary dialkylated intermediate, and then propose a mechanism for the reaction of that intermediate with urea to give aprobarbital.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 33

One way to determine the number of acidic hydrogens in a molecule is to treat the compound with NaOD in $\mathbf{D}_{2} \mathrm{O},$ isolate the product, and determine its molecular weight by mass spectrometry. For example, if cyclohexanone is treated with $\mathrm{NaOD}$ in $\mathrm{D}_{2} \mathrm{O},$ the product has $\mathrm{MW}=102 .$ Explain how this method works.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 34

When optically active $(R)$ - 2 -methylcyclohexanone is treated with either aqueous base or acid, racemization occurs. Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 35

Would you expect optically active ( $S$ )-3-methylcyclohexanone to be racemized on acid or base treatment in the same way as 2 -methylcyclohexanone (Problem 22.34 )? Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 36

When an optically active carboxylic acid such as $(R)$ - 2 -phenylpropanoic acid is brominated under Hell-Volhard-Zelinskii conditions, is the product optically active or racemic? Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 37

Fill in the reagents a-c that are missing from the following scheme:
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 38

Nonconjugated $\beta, \gamma$ -unsaturated ketones, such as 3 -cyclohexenone, are in an acid-catalyzed equilibrium with their conjugated $\alpha, \beta$ -unsaturated isomers. Propose a mechanism for this isomerization.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 39

The interconversion of unsaturated ketones described in Problem 22.38 is also catalyzed by base. Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 40

One consequence of the base-catalyzed isomerization of unsaturated ketones described in Problem 22.39 is that 2 -substituted 2 -cyclopentenones can be interconverted with 5 -substituted 2 -cyclopentenones. Propose a mechanism for this isomerization.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 41

Although 2 -substituted 2 -cyclopentenones are in a base-catalyzed equilibrium with their 5 -substituted 2 -cyclopentenone isomers (Problem 22.40 ), the analogous isomerization is not observed for 2 -substituted 2-cyclohexenones. Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 42

Using curved arrows, propose a mechanism for the following reaction, one of the steps in the metabolism of the amino acid alanine.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 43

Using curved arrows, propose a mechanism for the following reaction, one of the steps in the biosynthesis of the amino acid tyrosine.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 44

All attempts to isolate primary and secondary nitroso compounds result only in the formation of oximes. Tertiary nitroso compounds, however, are stable. Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 45

How would you synthesize the following compounds from cyclohexanone? More than one step may be required.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 46

The two isomers cis-and trans- 4 -tert-butyl-2-methylcyclohexanone are interconverted by base treatment. Which isomer do you think is more stable, and why?

Hailey Tomashek

Hailey Tomashek

Numerade Educator

Problem 47

The following synthetic routes are incorrect. What is wrong with each?
(EQUATION CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 48

Attempted Grignard reaction of cyclohexanone with tert-butylmagnesium bromide gives only about $1 \%$ yield of the expected addition product along with 9996 unreacted cyclohexanone. If $\mathrm{D}_{3} \mathrm{O}^{+}$ is added to the reaction mixture after a suitable period, however, the "unreacted" cyclohexanone is found to have one deuterium atom incorporated into it. Explain.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 49

One of the later steps in glucose biosynthesis is the isomerization of fructose 6-phosphate to glucose 6 -phosphate. Propose a mechanism, using acid or base catalysis as needed.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 50

The Favorskil reaction involves treatment of an $\alpha$ -bromo ketone with base to yield a ring-contracted product. For example, reaction of 2-bromocyclohexanone with aqueous NaOH yields cyclopentanecarboxylic acid. Propose a mechanism.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 51

Treatment of a cyclic ketone with diazomethane is a method for accomplishing a ring-expansion reaction. For example, treatment of cyclohexanone with diazomethane yields cycloheptanone. Propose a mechanism.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 52

Ketones react slowly with benzeneselenenyl chloride in the presence of HCl to yield $\alpha$ -phenylseleno ketones. Propose a mechanism for this acid-catalyzed $\alpha$ -substitution reaction.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 53

As far back as the 16 th century, South American Incas chewed the leaves of the coca bush, Erythroxylon coca, to combat fatigue. Chemical studies of Erythroxylon coca by Friedrich Wöhler in 1862 resulted in the discovery of cocaine, $\mathrm{C}_{17} \mathrm{H}_{21} \mathrm{NO}_{4},$ as the active component. Basic hydrolysis of cocaine leads to methanol, benzoic acid, and another compound called ecgonine, $\mathrm{C}_{9} \mathrm{H}_{15} \mathrm{NO}_{3}$. Oxidation of ecgonine with $\mathrm{CrO}_{3}$ yields a keto acid that readily loses $\mathrm{CO}_{2}$ on heating, giving tropinone.
(a) What is a likely structure for the keto acid?
(b) What is a likely structure for ecgonine, neglecting stereochemistry?
(c) What is a likely structure for cocaine, neglecting stereochemistry?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 54

The final step in an attempted synthesis of laurene, a hydrocarbon isolated from the marine alga Laurencia glandulifenc, involved the Wittig reaction shown. The product obtained, however, was not laurene but an isomer. Propose a mechanism to account for these unexpected results.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 55

The key step in a reported laboratory synthesis of sativene, a hydrocarbon isolated from the mold Helminthosporium sativum, involves the following base treatment of a keto tosylate. What kind of reaction is occurring? How would you complete the synthesis?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 56

Amino acids can be prepared by reaction of alkyl halides with diethyl acetamidomalonate, followed by heating the initial alkylation product with aqueous HCl. Show how you would prepare alanine, $\mathrm{CH}_{3} \mathrm{CH}\left(\mathrm{NH}_{2}\right) \mathrm{CO}_{2} \mathrm{H},$ one of the twenty amino acids found in proteins, and propose a mechanism for acid-catalyzed conversion of the initial alkylation product to the amino acid.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 57

Amino acids can also be prepared by a two-step sequence that involves HellVolhard-Zelinskil reaction of a carboxylic acid followed by treatment with ammonia. Show how you would prepare leucine, $\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CHCH}_{2} \mathrm{CH}\left(\mathrm{NH}_{2}\right) \mathrm{CO}_{2} \mathrm{H}$
and identify the mechanism of the second step.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 58

Heating carvone with aqueous sulfuric acid converts it into carvacrol. Propose a mechanism for the isomerization.
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 59

Sodium Pentothal is a short-acting barbiturate derivative used as a general anesthetic and known in popular culture as a truth serum. It is synthesized like other barbiturates (see the $A$ Deeper Look at the end of this chapter), using thiourea, $\left(\mathrm{H}_{2} \mathrm{N}\right)_{2} \mathrm{C}=\mathrm{S},$ in place of urea. How would you synthesize Sodium Pentothal?
(FIGURE CAN'T COPY)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator