22. Carboxylic Acid Derivatives: NAS

Nucleophilic Acyl Substitution Practice Problems

22. Carboxylic Acid Derivatives: NAS

Nucleophilic Acyl Substitution - Online Tutor, Practice Problems & Exam Prep

Nucleophilic Acyl Substitution Practice Problems

111 problems

1PRACTICE PROBLEM

Determine the major product of the reaction below.

2PRACTICE PROBLEM

Draw the major product of the reaction shown below.

3PRACTICE PROBLEM

Edman's degradation of a peptide forms thiazoline which can undergo rearrangement in dilute acid to phenylthiohydantoin (PTH) amino acid. Propose a mechanism for the rearrangement of the thiazoline shown below. (Hint: Thioesters react readily with nucleophiles.)

4PRACTICE PROBLEM

Complete the given reactions.

5PRACTICE PROBLEM

Identify the reagent(s) that can be used in the following reaction.

6PRACTICE PROBLEM

Draw the substitution product(s) of the given reaction.

7PRACTICE PROBLEM

The reaction of an acyl chloride with an aqueous solution of primary or secondary amine forms an amide as the major product. Predict the product formed when acetyl chloride reacts with trimethylamine.

8PRACTICE PROBLEM

Acetic acid is dissolved in isotopically labeled water (H ₂O¹⁸) with an acid catalyst. Draw the labeled product(s) formed.

9PRACTICE PROBLEM

Provide the major substitution product(s) of the reaction below.

10PRACTICE PROBLEM

What neutral nucleophile would you use to convert methyl propionate into N-ethylpropionamide?

11PRACTICE PROBLEM

Determine the identity of the major products obtained in the reaction between benzoyl chloride and each of the compounds shown below.

(i) methanol

(ii) potassium acetate

(iii) 2-methylaniline

12PRACTICE PROBLEM

Suggest a mechanism for this nucleophilic acyl substitution.

13PRACTICE PROBLEM

Show how to make each of the compounds shown below using the appropriate acyl chlorides and amines as your starting materials.

14PRACTICE PROBLEM

Determine the identity of products obtained in each of the reactions shown below.

15PRACTICE PROBLEM

Suggest a mechanism for this nucleophilic acyl substitution.

16PRACTICE PROBLEM

Suggest a plausible mechanism for the reaction shown below.

17PRACTICE PROBLEM

Suggest a plausible mechanism for the reaction shown below.

18PRACTICE PROBLEM

Suggest a plausible mechanism for the reaction shown below.

19PRACTICE PROBLEM

Under mild conditions, which of the proposed reactions below would take place quickly?

20PRACTICE PROBLEM

Show how to synthesize each of the compounds below using appropriate acyl chlorides and alcohols as the starting materials.
(i) methyl propionate
(ii) phenyl 2-methylhexanoate

21PRACTICE PROBLEM

Give the structures of the products and suggest a plausible mechanism for the reaction shown below.

22PRACTICE PROBLEM

Using an acid chloride as an intermediate, provide a reaction scheme to synthesize N-cyclopentylcyclopentanecarboxamide from cyclopentanecarboxylic acid and cyclopentanamine.

23PRACTICE PROBLEM

Provide a reaction scheme for the conversion of the given starting material to the nitrile shown below:

2-cyclohexylacetic acid → 2-cyclohexylacetonitrile

24PRACTICE PROBLEM

Propose a plausible synthesis that would efficiently carry out the following conversion. Use any necessary additional reagents.

25PRACTICE PROBLEM

Provide a reaction scheme for synthesizing the compound below, using the suitable carboxylic acid and amine.

26PRACTICE PROBLEM

Propose a reaction scheme for the synthesis of the specified compound below, utilizing the suitable carboxylic acid and amine.

27PRACTICE PROBLEM

Provide a plausible synthetic scheme for the following compound, which can be synthesized from a suitable carboxylic acid and amine.

28PRACTICE PROBLEM

Demonstrate how to synthesize the esters below from suitable alcohols and acyl chlorides:

i) <IMAGE>

ii) <IMAGE>

29PRACTICE PROBLEM

Illustrate the use of suitable amines and acyl chlorides to synthesize the amides below:

i) <IMAGE>

ii) <IMAGE>

30PRACTICE PROBLEM

Demonstrate the use of propionic anhydride and a suitable amine or alcohol to yield the following:

i) <IMAGE>

ii) <IMAGE>

31PRACTICE PROBLEM

Provide a reaction scheme to synthesize the following compounds. Note: The reaction scheme may involve more than one step.

(i) cyclopentanamine → N-cyclopentylacetamide

(ii) bromocyclopentane → dicyclopentylmethanol

32PRACTICE PROBLEM

What is the product of the reaction below?

33PRACTICE PROBLEM

Draw the structures of the expected products for the reaction below.

34PRACTICE PROBLEM

Draw the structure of the product formed from the reaction below.

35PRACTICE PROBLEM

Give the structure of the product formed from the reaction below.

36PRACTICE PROBLEM

Provide a reaction scheme to accomplish the synthesis shown below in good yield.

37PRACTICE PROBLEM

Phosgene is the acid chloride of carbonic acid. It can react twice just like other acid chlorides.

What is the product of the reaction of phosgene with excess butan-1-ol?

38PRACTICE PROBLEM

(i) The addition of one mole of 3-methylbutanoyl chloride to a liter of triethylamine resulted in a vigorous exothermic reaction. What is the mechanism for this reaction?

(ii) Once the previous mixture has cooled, one mole of propan-1-ol is added. This resulted in another vigorous exothermic reaction that produced triethylamine, triethylammonium chloride, and propyl 3-methylbutanoate. What is the mechanism for this reaction?

39PRACTICE PROBLEM

Propose a mechanism for the reaction between 3-methylbenzoic acid and propionyl chloride to yield 3-methylbenzoic propionic anhydride and hydrochloric acid. Let the oxygen in the hydroxyl group of 3-methylbenzoic acid serve as the nucleophile to attack the carbonyl carbon of the propionyl chloride.

<IMAGE>

40PRACTICE PROBLEM

Suggest a mechanism for the reaction between m-toluidine and methyl acetate to yield N-(m-tolyl)acetamide and methanol. In the proposed mechanism, identify the leaving group and determine whether it is suitable for an S_N2 reaction.

<IMAGE>

41PRACTICE PROBLEM

Outline a mechanism when benzyl propionate and isopropylamine react. Include the structure of the transition state when the leaving group departs. Also, identify the nucleophile and the leaving group.

42PRACTICE PROBLEM

Consider the following acid-catalyzed reaction:

Suggest a mechanism for the reaction. Why does a drop of sulfuric acid significantly speed up the rate of the reaction?

43PRACTICE PROBLEM

Describe how the following compounds can be synthesized using anhydride as a starting material. Why is an anhydride a more suitable starting material than an acid chloride?

(i) glutaric acid monamide

(ii) glutaric acid monoethyl ester

44PRACTICE PROBLEM

Determine the major products obtained from the reaction of cyclopentanecarbonyl chloride with each of the reagents listed below:

(i) toluene and aluminum chloride, followed by water

(ii) excess cyclopentylmagnesium bromide followed by treatment with a dilute acid

(iii) LiAlH(O-t-Bu)₃

45PRACTICE PROBLEM

Arrange the carboxylic acid derivatives listed below in decreasing order of reactivity toward nucleophilic attack at C=O with a strong nucleophile like methoxide.

46PRACTICE PROBLEM

Propose the most appropriate reactants to use for the conversion below.

47PRACTICE PROBLEM

Show the products formed in the reactions given below.

(1)

(2)

48PRACTICE PROBLEM

Diethyl carbonate is an easy-to-handle liquid reagent that is widely utilized in synthesis. Show how you would synthesize propoxur insecticide using diethyl carbonate as the starting material.

49PRACTICE PROBLEM

The reaction shown below converts the carboxylic acid into an N-hydroxysuccinimide (NHS) ester to activate it for coupling with an amine. Is a NHS ester more reactive than a simple alkyl ester? Why?

50PRACTICE PROBLEM

4-acetylbenzoic acid is an isomer of aspirin, an anti-inflammatory medicine. Show how you would synthesize 4-acetylbenzoic acid from phenol.

51PRACTICE PROBLEM

Propose the most appropriate reagent(s) to use for the following conversion.

52PRACTICE PROBLEM

Determine the product formed in the reaction given below:

ethoxy benzene + glutaric anhydride and aluminum chloride, followed by water

53PRACTICE PROBLEM

Propose the multistep synthesis of the following transformation. Use any necessary reagents and solvents.

54PRACTICE PROBLEM

What reagents are required to produce the following compound using the given starting material?

55PRACTICE PROBLEM

The Ritter reaction occurs when nitrile and alcohol react in the presence of an acid to form N-substituted amide. Provide an appropriate mechanism for the Ritter reaction depicted below.

56PRACTICE PROBLEM

The Ritter reaction occurs when nitrile and secondary or tertiary alcohol reacts in the presence of an acid to form N-substituted amide. Explain why the Ritter reaction does not work with primary alcohols.

57PRACTICE PROBLEM

The reaction of a nitrile with a secondary or tertiary alcohol to produce an N-substituted amide in the presence of an acid is called the Ritter reaction. The reaction includes the nucleophilic addition of a nitrile to a carbenium ion. What is the key difference between the Ritter reaction and the amide formation through acid-catalyzed hydrolysis of a nitrile?

58PRACTICE PROBLEM

i) Identify the reactions that will not produce the given carbonyl product.
ii) Which reactions from part (i) will occur upon addition of an acid catalyst?

59PRACTICE PROBLEM

i) Identify the reactions that will not produce the given carbonyl product.
ii) Which reactions from part (i) will occur upon addition of an acid catalyst?

60PRACTICE PROBLEM

Explain why an acid cannot increase the rate of aminolysis of an ester.

61PRACTICE PROBLEM

Explain why a base cannot increase the rate of aminolysis of an ester.

A. Because the base would protonate the amine and it would lose its nucleophilicity.

B. Because the base would compete with the amine for the nucleophilic acyl substitution.

C. Because the base would deprotonate the amine and it would lose its nucleophilicity.

D. None of these.

62PRACTICE PROBLEM

Arrange the following esters in increasing order of their reactivity towards the first step of the nucleophilic acyl substitution.

63PRACTICE PROBLEM

Arrange the following esters in increasing order of their reactivity towards the second step of the nucleophilic acyl substitution.

64PRACTICE PROBLEM

Rank the following compounds by increasing reactivity of their C=O bond towards strong nucleophiles like ethoxide.

65PRACTICE PROBLEM

Show how you would convert 2-methylcyclohexanol to the following products.

a. 2-methylcyclohexylpropionate

b. 1-bromo-1-methylcyclohexane

66PRACTICE PROBLEM

Draw the product expected in the following multistep reaction.

67PRACTICE PROBLEM

Draw the product of the multistep synthesis reaction shown below.

68PRACTICE PROBLEM

Show how the following conversion can be accomplished.

69PRACTICE PROBLEM

Propose a synthetic pathway to produce each of the following compounds using an ester with no more than eight carbons and other necessary reagents.

70PRACTICE PROBLEM

Show how the following syntheses can be carried out by acylation–reduction of the given amines.

a. N-benzylpyrrolidine from pyrrolidine

b. N-ethylaniline from aniline

71PRACTICE PROBLEM

Determine the ion(s) that would produce an anhydride faster:

72PRACTICE PROBLEM

Determine the product formed in a reaction between propanamide and OH^-. Hint: pK_a(NH₃) = 38.0, and pK_a(H₂O) = 15.7.

73PRACTICE PROBLEM

What would be the product of the acyl substitution reaction in which a weaker base than the substituent linked to the acyl group is used?

74PRACTICE PROBLEM

If the base is stronger than the substituent linked to the acyl group in the tetrahedral intermediate, determine the product of an acyl substitution reaction.

75PRACTICE PROBLEM

Given below is the table with the pK_a values of the conjugate acids of several leaving groups. Based on the table, predict the product of the following reaction.

76PRACTICE PROBLEM

Using the pK_a values provided in the table below, predict the product of the following reaction.

77PRACTICE PROBLEM

Which neutral nucleophile, starting with propionyl bromide, would you utilize to produce the following compound?

78PRACTICE PROBLEM

Which neutral nucleophile would be required to synthesize the compound given below if the starting material is propionyl bromide?

79PRACTICE PROBLEM

If propionyl bromide is chosen as the starting material, determine the neutral nucleophile needed to produce the following compound.

80PRACTICE PROBLEM

Determine the neutral nucleophile needed to produce the given compound from propionyl bromide.

81PRACTICE PROBLEM

Draw the mechanism of the aminolysis of p-tolyl acetate using ethylamine.

82PRACTICE PROBLEM

Illustrate the mechanism of the reaction between acetamide and methanol in an acid-catalyzed reaction to form an ester.

83PRACTICE PROBLEM

Illustrate the mechanism of the reaction between propionic anhydride and water.

84PRACTICE PROBLEM

Which of these reactions involves the loss of the carboxylate anion from the tetrahedral intermediate without deprotonation prior to the elimination step? Explain.

85PRACTICE PROBLEM

Suggest a suitable mechanism for the reaction between glutaric acid and ethanoic anhydride to form glutaric anhydride at a neutral pH.

86PRACTICE PROBLEM

Determine how ethanoic anhydride promotes the creation of glutaric anhydride.

87PRACTICE PROBLEM

What is the product formed in a reaction between 4-methylbenzoyl chloride and sodium hydroxide?

88PRACTICE PROBLEM

Which substances are produced when 4-methylbenzoyl chloride reacts with cyclopentanol?

89PRACTICE PROBLEM

Determine the product for the reaction of 4-methylbenzoyl chloride with isobutyl alcohol.

90PRACTICE PROBLEM

What is the product formed when 4-methylbenzoyl chloride reacts with sodium acetate?

91PRACTICE PROBLEM

What would be the product(s) formed for the hydrolysis reaction given?

92PRACTICE PROBLEM

Determine the product(s) formed in the given reaction at neutral pH.

glutaric acid + propionyl chloride (2 eq.)

93PRACTICE PROBLEM

What would be the product(s) formed in the given reaction?

isopropyl carbamate + ethylamine

94PRACTICE PROBLEM

Show how the following conversion can be accomplished using any necessary reagents.

95PRACTICE PROBLEM

Propose a suitable mechanism for the reaction given below.

96PRACTICE PROBLEM

Methyl isobutyrate can be produced from isobutyric acid using diazomethane.

Does the following reaction mechanism correspond to this reaction?

97PRACTICE PROBLEM

Illustrate the mechanism of the reaction between propanoyl chloride and water to produce propanoic acid.

98PRACTICE PROBLEM

Illustrate the mechanism when di-tert-butyl dicarbonate, reacts with the simplest amino acid, glycine.

99PRACTICE PROBLEM

What is the product of the reaction shown below?

100PRACTICE PROBLEM

A carboxylic acid needs to be activated before it can be coupled with an amine. This is often achieved by converting the acid into an N-hydroxysuccinimide (NHS) ester as shown below. Suggest a mechanism for the transformation.

101PRACTICE PROBLEM

Provide a reaction scheme showing the synthesis of the ester compounds listed below from their corresponding acyl chloride and alcohol.

i. benzyl cyclopentanecarboxylate

ii. cyclopentyl cyclohexanecarboxylate

102PRACTICE PROBLEM

Determine the product produced by each of the reactions given below.

i. p-cresol + propionic anhydride

ii. p-cresol + acetic formic anhydride

103PRACTICE PROBLEM

What is the product of the reaction shown below?

104PRACTICE PROBLEM

A carboxylic acid can be activated for coupling with an amine by converting it to an N-hydroxysuccinimide (NHS) ester, as shown below. Suggest a mechanism for the reaction that occurs between ethanamine and the NHS ester.

105PRACTICE PROBLEM

Give the product of the reaction shown below:

106PRACTICE PROBLEM

Show how the following ketone can be produced by a Friedel-Crafts acylation using the given carboxylic acid.

107PRACTICE PROBLEM

Provide the product of the reaction shown below:

108PRACTICE PROBLEM

Phosgene is the acid chloride of carbonic acid. It can react twice, just like other acid chlorides. What is the product of the reaction of phosgene with 1 equivalent of ethanol, followed by 1 equivalent of cyclopentanamine?

109PRACTICE PROBLEM

Show how the following synthesis can be carried out:

cyclohexylmethanol → cyclohexylmethyl acetate

110PRACTICE PROBLEM

Show how the following synthesis can be accomplished. (Note: The conversion might involve multiple steps.)

benzoic acid → benzonitrile

111PRACTICE PROBLEM

Show how the following transformation can be accomplished:

3-methylbutan-2-amine → N-(3-methylbutan-2-yl)formamide