Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions

21-35 Pivalic mixed anhydrides are often used to form amide bonds between amino acids. Unlike with a symmetrical anhydride, this reaction is highly regioselective, with the nucleophile adding only to the amino-acid carbonyl. Provide the complete mechanism for the reaction below and explain the regioselectivity.

Given IUPAC names for the following substances:

Draw structures corresponding to the following names:
 (a) Phenyl benzoate
 (b) N-Ethyl-N-methylbutanamide
 (c) 2,4-Dimethylpentanoyl chloride
 (d) Methyl 1-methylcyclohexanecarboxylate
 (e) Ethyl 3-oxopentanoate
 (f) Methyl p-bromobenzenethioate
 (g) Formic propanoic anhydride
(h) cis-2-Methylcyclopentanecarbonyl bromide

Show the mechanism of the following nucleophilic acyl substitution reaction, using curved arrows to indicate the electron flow in each step:

Predict the products of the following nucleophilic acyl substitution reactions:

The following structure represents a tetrahedral alkoxide ion intermediate formed by the addition of a nucleophile to a carboxylic acid derivative. Identify the nucleophile, the leaving group, the starting acid derivative, and the ultimate product.

If the following molecule is treated with acid catalyst, an intramolecular esterification reaction occurs. What is the structure of the product? (Intramolecular means within the same molecule.)

How might you prepare the following esters from the corresponding acids?

How might you prepare the following esters using a nucleophilic acyl substitution reaction of an acid chloride?

(a) ${\mathbf{CH}}_{\mathbf{3}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CO}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{3}}$

(b) ${\mathbf{CH}}_{\mathbf{3}}{\mathbf{CO}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{3}}$

(c) Ethyl benzoate.

Write the mechanism of the reaction just shown between 3,4,5-trimethoxybenzoyl chloride and morpholine to form trimetozine. Use curved arrows to show the electron flow in each step.

Question: How could you prepare the following amides using an acid chloride and an amine or ammonia?

How could you prepare the following ketones by reaction of an acid chloride with a lithium diorganocopper reagent?

Write the mechanism of the reaction between p-hydroxyaniline and acetic anhydride to prepare acetaminophen.

What product would you expect from reaction of one equivalent of methanol with a cyclic anhydride, such as phthalic anhydride   (1,2-benzenedicarboxylic anhydride)? What is the fate of the second “half” of the anhydride?

Why is the saponification of an ester irreversible? In other words, why doesn’t treatment of a carboxylic acid with an alkoxide ion yield an ester?

What product would you expect from the reaction of butyrolactone with LiAlH4? With DIBAH?

Show the products you would obtain by reduction of the following esters with LiAlH₄:

(a)                                                                  (b)    

What ester and what Grignard reagent might you start with to prepare the following alcohols?

a.

b.

c.

How would you convert N-ethylbenzamide to each of the following products?

 (a) Benzoic acid (b) Benzyl alcohol (c) ${\mathbf{C}}_{\mathbf{6}}{\mathbf{H}}_{\mathbf{5}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{NHCH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{3}}$

How would you use the reaction of an amide with LiAlH₄ as the key step in going from bromocyclohexane to (N,N-dimethylaminomethyl)cyclohexane? Write all the steps in the reaction sequence.

Write the mechanism of the reaction shown in Figure 21-9 between coenzyme A and acetyl adenylate to give acetyl CoA.

Draw structures of the step-growth polymers you would expect to obtain from the following reactions:

Kevlar, a nylon polymer prepared by reaction of 1,4-benzenedicarboxylic acid (terephthalic acid) with 1,4-benzenediamine (p-phenylenediamine), is so strong that it’s used to make bulletproof vests. Draw the structure of a segment of Kevlar.

What kinds of functional groups might compounds have if they show the following IR absorptions? 

(a) Absorption at 1735 cm^-1

(b) Absorption at 1810 cm^-1

(c) Absorptions at 2500 to 3300 cm^-1 and 1710 cm^-1

(d) Absorption at 1715 cm^-1

Propose structures for compounds that have the following formulas and IR absorptions:

(a) C₆H₁₂O₂, 1735 cm^-1 

(b) C₄H₉NO, 1650 cm^-1 

(c) C₄H₅ClO, 1780 cm^-1

21-72 Phenyl 4-aminosalicylate is a drug used in the treatment of tuberculosis. Propose a synthesis of this compound starting from 4-nitrosalicylic acid.

21-73 N,N-Diethyl-m-toluamide (DEET) is the active ingredient in manyinsect repellent preparations. How might you synthesize this substancefrom m-bromotoluene?

21-74 Tranexamic acid, a drug useful against blood clotting, is prepared commercially from p-methylbenzonitrile. Formulate the steps likely to beused in the synthesis. (Don't worry about cis-trans isomers; heating to300 °C interconverts the isomers.)

21-75 One frequently used method for preparing methyl esters is by reactionof carboxylic acids with diazomethane, ${\mathbf{\text{CH}}}_{\mathbf{\text{2}}}{\mathbf{\text{N}}}_{\mathbf{\text{2}}}$

The reaction occurs in two steps: (1) protonation of diazomethane bythe carboxylic acid to yield methyldiazonium ion,, ${\mathbf{\text{CH}}}_{\mathbf{\text{3}}}{{\mathbf{\text{N}}}_{\mathbf{\text{2}}}}^{\mathbf{+}}$plus a carboxylate ion; and (2) reaction of the carboxylate ion with ${\mathbf{\text{CH}}}_{\mathbf{\text{3}}}{{\mathbf{\text{N}}}_{\mathbf{\text{2}}}}^{\mathbf{+}}$ .
 (a) Draw two resonance structures of diazomethane, and account forstep 1.
(b) What kind of reaction occurs in step 2?

When an amide is formed from an acid chloride or an anhydride, two moles of base are required. However, when an ester is used as the starting material, only one equivalent of base is needed. Explain the reactivity in terms of basicity of the leaving groups.

Epoxy adhesives are prepared in two steps. S_N2 reaction of the disodium salt of bisphenol A with epichlorohydrin forms a “Pre-polymer,” which is then “Cured” by treatment with a triamine such as H₂NCH₂CH₂NHCH₂CH₂NH_2.

Draw structures to show how the addition of the triamine results in a strengthening of the polymer.

Name the following compounds:

a.

b.

How would you prepare the following compounds starting with an appropriate carboxylic acid and any other reagents needed? (Reddish brown = Br.)

a.

b.

The following structure represents a tetrahedral alkoxide-ion intermediate formed by addition of a nucleophile to a carboxylic acid derivative. Identify the nucleophile, the leaving group, the starting acid derivative, and the ultimate product (green = Cl).

21-30 Electrostatic potential maps of a typical amide (acetamide) and an acyl azide (acetyl azide) are shown. Which of the two do you think is more reactive in nucleophilic acyl substitution reactions? Explain.
 

21-31 Predict the product(s) and provide the mechanism for each reaction below.

21-32 Predict the product(s) and provide the mechanism for each reaction below.

21-33 Predict the product(s) and provide the mechanism for each reaction below.

21-34 Predict the product(s) and provide the mechanism for each reaction below.

21-36 When 4-dimethylaminopyridine (DMAP) is added in catalytic amounts to acetic anhydride and an alcohol, it significantly increases the rate of ester formation. The process begins with a reaction between acetic anhydride and DMAP to form a highly reactive acetylpyridinium intermediate that is more reactive than acetic anhydride itself. Propose a mechanism for this process that includes the formation and reaction of the acetylpyridinium intermediate.

21-37 Fats are biosynthesized from glycerol 3-phosphate and fatty-acyl CoA's by a reaction sequence that begins with the following step. Show the mechanism of the reaction.

21-38 Treatment of an a-amino acid with DCC yields a 2,5-diketopiperazine.Propose a mechanism.

21-39 Succinic anhydride yields the cyclic imide succinimide when heated with ammonium chloride at 200°C. Propose a mechanism for this reaction. Why do you suppose such a high reaction temperature is required?
 

The hydrolysis of a biological thioester to the corresponding carboxylate is often more complex than the overall result might suggest. The conversion of succinyl CoA to succinate in the citric acid cycle, for instance, occurs by initial formation of an acyl phosphate, followed by reaction with guanosine diphosphate (GDP, a relative of adenosine diphosphate [ADP]) to give succinate and guanosine triphosphate (GTP, a relative of ATP). Suggest mechanisms for both steps.
 

One step in the gluconeogenesis pathway for the biosynthesis of glucose is the partial reduction of 3-phosphoglycerate to give glyceraldehyde 3-phosphate. The process occurs by phosphorylation with ATP to give 1,3-bisphosphoglycerate, reaction with a thiol group on the enzyme to give an enzyme-bound thioester, and reduction with NADH. Suggest mechanisms for all three reactions.
 

Bacteria typically develop a resistance to penicillins and other β-lactam antibiotics (see Something Extra in this chapter) due to bacterial synthesis of β -lactamase enzymes. Tazobactam, however, is able to inhibit the activity of the β -lactamase by trapping it, thereby preventing a resistance from developing.

(a) The first step in trapping is the reaction of a hydroxyl group on the β -lactamase to open the β -lactam ring of tazobactam. Show the mechanism.
 (b) The second step is opening the sulfur-containing ring in tazobactam to give an acyclic imine intermediate. Show the mechanism.
(c) Cyclization of the imine intermediate gives the trapped β-lactamase product. Show the mechanism.

21-43 The following reaction, called the benzilic acid rearrangement, takes place by typical carbonyl group reactions. Propose a mechanism (Ph=phenyl).

21-45 Give IUPAC names for the following compounds:

21-46 Draw structures corresponding to the following names

1. p-Bromophenylacetamide
2. m-Benzoylbenzamide
3. 2,2-Dimethylhexanamide
4. Cyclohexyl cyclohexanecarboxylate
5. Ethyl 2-cyclobutenecarboxylate
6. Succinic anhydride

21-47 Draw and name compounds that meet the following descriptions:
 (a) Three acid chlorides having the formula ${\mathrm{C}}_6{\mathrm{H}}_9\mathrm{ClO}$
(b) Three amides having the formula $C_7{H}_{\mathit{11}}NO$