Chapter 11 Solutions to Problems – Carboxylic Acids and Derivatives: Nucleophilic Acyl Substitution Reactions

Kirsten Kramer; Cassandra Lilly

11 Chapter 11 Solutions to Problems – Carboxylic Acids and Derivatives: Nucleophilic Acyl Substitution Reactions

Chapter 11 – Carboxylic Acids and Derivatives: Nucleophilic Acyl Substitution Reactions

Solutions to Problems

11.1

Carboxylic acids are named by replacing –e of the corresponding alkane with –oic acid.

The carboxylic acid carbon is C1.

When –CO₂H is a substituent of a ring, the suffix –carboxylic acid is used; the carboxyl carbon is not numbered in this system.

(a)

(b)

(c)

(d)

(e)

(f)

11.2

(a)

(b)

(c)

(d)

(e)

(f) CH₃CH₂CH=CHCN

2-Pentenenitrile

11.3	Table 11.1 lists the suffixes for naming carboxylic acid derivatives. The suffixes used when the functional group is part of a ring are in parentheses.
	(a)	(b)
	(c)	(d)
	(e)	(f)
	(g)	(h)
	(i)

11.4	(a)	(b)
	(c)	(d)
	(e)	(f)
	(g)	(h)

11.5

Naphthalene is insoluble in water and benzoic acid is only slightly soluble. The salt of benzoic acid is very soluble in water, however, and we can take advantage of this solubility in separating naphthalene from benzoic acid.

Dissolve the mixture in an organic solvent, and extract with a dilute aqueous solution of sodium hydroxide or sodium bicarbonate, which will neutralize benzoic acid.

Naphthalene remains in the organic layer, and all the benzoic acid, now converted to the benzoate salt, is in the aqueous layer. To recover benzoic acid, remove the aqueous layer, acidify it with dilute mineral acid, and extract with an organic solvent.

11.6

You would expect lactic acid to be a stronger acid because the electron-withdrawing inductive effect of the hydroxyl group can stabilize the lactate anion.

11.7

The pK_a1 of oxalic acid is lower than that of a monocarboxylic acid because the carboxylate anion is stabilized both by resonance and by the electron-withdrawing inductive effect of the nearby second carboxylic acid group.

The pK_a2 of oxalic acid is higher than pK_a1 because an electrostatic repulsion between the two adjacent negative charges destabilizes the dianion.

11.8

Remember that electron-withdrawing groups increase carboxylic acid acidity, and electron-donating groups decrease carboxylic acid acidity. Benzoic acid is more acidic than acetic acid.

11.9

11.10

11.11	Use Figure 11.4 if you need help.
	Most reactive ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ Least reactive
	(a)
	(b)
	The most reactive acyl derivatives contain strongly electron-withdrawing groups in the part of the structure that is to be the leaving group.

11.12	Identify the nucleophile (boxed) and the leaving group (circled), and replace the leaving group by the nucleophile in the product.
	(a)
	(b)
	(c)
	(d)

11.13

The structure represents the tetrahedral intermediate in the reaction of methyl cyclopentylacetate with hydroxide, a nucleophile. The products are cyclopentylacetate anion and methanol.

11.14	In Fischer esterification, an alcohol undergoes a nucleophilic acyl substitution with a carboxylic acid to yield an ester. The mineral acid catalyst makes the carboxyl group of the acid more electrophilic. Predicting the products is easier if the two reagents are positioned so that the reacting functional groups point towards each other.
	(a)
	(b)
	(c)

11.15

Under Fischer esterification conditions, many hydroxycarboxylic acids can form intramolecular esters (lactones).

11.16

The alcohol product can be formed by reduction of a carboxylic acid with LiAlH₄. The carboxylic acid can be synthesized either by Grignard carboxylation or by nitrile hydrolysis. The product can also be formed by a Grignard reaction between benzyl bromide and formaldehyde.

11.17

After treating the initial alcohol with PBr₃, the same steps as used in the previous problem can be followed. A Grignard reaction between the cycloalkylmagnesium bromide and formaldehyde also yields the desired product.

11.18	Pyridine neutralizes the HCl byproduct by forming pyridinium chloride. This neutralization removes from the product mixture acid that might cause side reactions. As mentioned previously, positioning the reacting groups so that they face each other makes it easier to predict the products.
	(a)
	(b)
	(c)

11.19

As explained in the text, only simple, low boiling alcohols are convenient to use in the Fischer esterification reaction. Thus, reaction of cyclohexanol with benzoyl chloride is the preferred method for preparing cyclohexyl benzoate.

11.20

11.21	An extra equivalent of base must be added to neutralize the acid produced in these reactions. In (a) and (b), two equivalents of the amine may be used in place of NaOH.
	(a)
	(b)
	(c)

11.22
	Step 1:	Nucleophilic addition of p-hydroxyaniline.
	Step 2:	Deprotonation by hydroxide.
	Step 3:	Loss of acetate ion.

11.23

The second half of the anhydride becomes a carboxylic acid.

11.24

Acidic hydrolysis of an ester is a reversible reaction because the products are an alcohol and a carboxylic acid. Basic hydrolysis of an ester is irreversible because its products are an alcohol and a carboxylate anion, which has a negative charge and does not react with nucleophiles.

11.25

11.26	Lithium aluminum hydride reduces an ester to form two alcohols.
	(a)
	(b)

11.27

Remember that Grignard reagents can only be used with esters to form a tertiary alcohol that has two identical substituents. Identify these two substituents, which come from the Grignard reagent, and work backward to select the ester (the alkyl group of the ester is unimportant).

11.28

(c)

11.29

(a)

This symmetrical ketone can be synthesized by a Grignard reaction between propanenitrile and ethylmagnesium bromide.

(b)

p-Nitroacetophenone can be synthesized by either of two Grignard routes.

11.30

Once you realize that the product results from a Grignard reaction with a nitrile, this synthesis is easy.

11.31

Even though the entire molecule of coenzyme A is biologically important, we are concerned in this problem only with the –SH group. The remainder of the structure is represented here as “R”.

Step 1:

Nucleophilic addition of the –SR group of CoA (after deprotonation) to acetyl adenylate to form a tetrahedral intermediate.

Step 2:

Loss of adenosine monophosphate.

11.32	In each example, if n molecules of one component react with n molecules of the other component, a polymer with n repeating units is formed, and 2n small molecules are formed as byproducts; these are shown in each reaction.
	(a)
	(b)
	(c)

11.33

Additional Problems

Visualizing Chemistry

11.34

(a)

(b)

(c)

(d)

11.35

(a)

(b)

(a) p-Bromobenzoic acid is more acidic than benzoic acid because the electron-withdrawing bromine stabilizes the carboxylate anion.

(b) This p-substituted aminobenzoic acid is less acidic than benzoic acid because the electron-donating group destabilizes the carboxylate anion.

11.36

Nitrile hydrolysis can’t be used to synthesize the above carboxylic acid because the tertiary halide precursor (shown on the right) doesn’t undergo S_N2 substitution with cyanide. Grignard carboxylation also can’t be used because the acidic hydroxyl hydrogen interferes with formation of the Grignard reagent. If the hydroxyl group is protected, however, Grignard carboxylation can take place.

11.37

The electrostatic potential maps show that the aromatic ring of anisole is more electron-rich (red) than the aromatic ring of thioanisole, indicating that the methoxyl group is more strongly electron-donating than the methylthio group. Since electron-donating groups decrease acidity, p-(methylthio)benzoic acid is likely to be a stronger acid than p-methoxybenzoic acid.

Mechanism Problems

11.38

(a)

Mechanism:

(b)

Mechanism:

11.39

(a)

Mechanism:

(b)

Mechanism:

11.40

(a)

Mechanism:

(b)

Mechanism:

Naming Carboxylic Acids and Nitriles

11.41

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

11.42

(a)	(b)
	HO₂CCH₂CH₂CH₂CH₂CH₂CO₂H Heptanedioic acid
(c)	(d)

(e)	(f)
	(C₆H₅)₃CCO₂H Triphenylacetic acid
(g)	(h)

11.43

(a)

(b)

11.44

11.45

Acidity of Carboxylic Acids

11.46

Less acidic ———-> More acidic

(a)

CH₃CO₂H < HCO₂H < HO₂C – CO₂H

Acetic acid Formic acid Oxalic acid

(b)

p-Bromobenzoic acid < p-Nitrobenzoic acid < 2,4-Dinitrobenzoic acid

(weakly electron- (strongly electron- (two strongly electron-

withdrawing substituent) withdrawing substituent) withdrawing substituents)

(c)

FCH₂CH₂CO₂H < ICH₂CO₂H < FCH₂CO₂H

In (c), the strongest acid has the most electronegative atom next to the carboxylic acid group. The next strongest acid has a somewhat less electronegative atom next to the carboxylic acid group. The weakest acid has an electronegative atom two carbons away from the carboxylic acid group.

11.47

Remember that the conjugate base of a weak acid is a strong base. In other words, the stronger the acid, the weaker the base derived from that acid.

Less basic —————> More basic

(a)

Mg(OAc)₂ < Mg(OH)₂ < H₃C^– MgBr⁺

Acetic acid is a much stronger acid than water, which is a much, much stronger acid than methane. The order of base strength is just the reverse.

(b)

Sodium p–nitrobenzoate < Sodium benzoate < HC≡C^– Na⁺

p-Nitrobenzoic acid is stronger than benzoic acid, which is much stronger than acetylene.

(c)

HCO₂^–Li⁺ < HO^–Li⁺ < CH₃CH₂O^– Li⁺

LiOH and LiOCH₂CH₃ are very similar in basicity

11.48

(a)

K_a = 8.4 × 10^–4 for lactic acid

pK_a = –log (8.4 × 10^–4) = 3.08

(b)

K_a = 5.6 × 10^–6 for acrylic acid

pK_a = –log (5.6 × 10^–6) = 5.25

11.49

(a)

pK_a = 3.14 for citric acid

K_a = 10^–3.14 = 7.2 × 10^–4

(b)

pK_a = 2.98 for tartaric acid

K_a = 10^–2.98 = 1.0 × 10^–3

11.50

Inductive effects of functional groups are transmitted through σ bonds. For oxalic acid, the electron-withdrawing inductive effect of one carboxylic acid group decreases the acidity of the remaining group. However, as the length of the carbon chain increases, the effect of one functional group on another decreases. In this example, the influence of the second carboxylic acid group on the ionization of the first is barely felt by succinic and adipic acids.

Reactions of Carboxylic Acids and Nitriles

11.51

11.52

11.53

(a)

(b)

(c)

11.54

(a)

(b)

11.55

In (c), the acidic proton reacts with the Grignard reagent to form methane, for no net reaction.

11.56

General Problems

11.57

2-Chloro-2-methylpentane is a tertiary alkyl halide and ^–CN is a base. Instead of the desired S_N2 reaction of cyanide with a halide, E2 elimination occurs and yields 2-methyl-2-pentene.

11.58

11.59

As we have seen throughout this book, the influence of substituents on reactions can be due to inductive effects and/or resonance effects. For m-hydroxybenzoic acid, the negative charge of the carboxylate anion is stabilized by the electron-withdrawing inductive effect of –OH, making this isomer more acidic. For p-hydroxybenzoic acid, the negative charge of the anion is destabilized by the electron-donating resonance effect of –OH that acts over the π electron system of the ring but is not important for m-substituents.