Skip to main content
Ch. 24 - Amino Acids, Peptides, and Proteins
Wade - Organic Chemistry 9th Edition
Wade9th EditionOrganic ChemistryISBN: 9780135213728Not the one you use?Change textbook
All textbooksWade 9th EditionCh. 24 - Amino Acids, Peptides, and ProteinsProblem 45b
Chapter 24, Problem 45b

There are many methods for activating a carboxylic acid in preparation for coupling with an amine. The following method converts the acid to an N-hydroxysuccinimide (NHS) ester.
Reaction mechanism showing the conversion of a carboxylic acid to an NHS ester with an amine.
(b) Propose a mechanism for the reaction shown.

Verified step by step guidance
1
Step 1: Identify the reactants and products in the reaction. The reactants are a carboxylic acid (R-COOH) and N-hydroxysuccinimide (NHS) activated by trifluoroacetic anhydride (CF3CO)2O in the presence of triethylamine (Et3N). The products are an NHS ester and trifluoroacetic acid (CF3COOH).
Step 2: Recognize the role of trifluoroacetic anhydride. It acts as an activating agent, converting the carboxylic acid into a reactive intermediate that facilitates the formation of the NHS ester.
Step 3: Propose the first step of the mechanism. The carboxylic acid reacts with trifluoroacetic anhydride, leading to the formation of an acyl trifluoroacetate intermediate. This occurs via nucleophilic attack of the carboxylic acid oxygen on the carbonyl carbon of trifluoroacetic anhydride, followed by elimination of trifluoroacetate.
Step 4: Propose the second step of the mechanism. The acyl trifluoroacetate intermediate reacts with N-hydroxysuccinimide (NHS). The nucleophilic oxygen of NHS attacks the carbonyl carbon of the acyl intermediate, leading to the formation of the NHS ester and trifluoroacetic acid as a byproduct.
Step 5: Highlight the role of triethylamine (Et3N). Triethylamine acts as a base to neutralize any acidic byproducts formed during the reaction, ensuring the reaction proceeds efficiently.

Verified video answer for a similar problem:

This video solution was recommended by our tutors as helpful for the problem above.
Video duration:
9m
Was this helpful?

Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Carboxylic Acid Activation

Carboxylic acids can be activated for coupling reactions by converting them into more reactive derivatives. One common method is the formation of an N-hydroxysuccinimide (NHS) ester, which enhances the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack by amines.
Recommended video:
Guided course
04:20
Carboxylic Acids Nomenclature

N-Hydroxysuccinimide (NHS) Ester Formation

The NHS ester is formed through the reaction of a carboxylic acid with N-hydroxysuccinimide in the presence of a coupling agent. This reaction results in the formation of a stable NHS ester, which can facilitate the subsequent nucleophilic attack by an amine, leading to the formation of an amide bond.
Recommended video:
2:21
Synthesis of Amino Acids: N-Phthalimidomalonic Ester Synthesis Example 2

Mechanism of Nucleophilic Acyl Substitution

The mechanism of nucleophilic acyl substitution involves the nucleophile attacking the electrophilic carbon of the carbonyl group, leading to the formation of a tetrahedral intermediate. This intermediate can then collapse, expelling a leaving group and forming a new bond, such as an amide bond in the case of coupling with an amine.
Recommended video:
Guided course
01:47
Nucleophiles and Electrophiles can react in Substitution Reactions.
Related Practice
Textbook Question

Sometimes chemists need the unnatural D enantiomer of an amino acid, often as part of a drug or an insecticide. Most L-amino acids are isolated from proteins, but the D-amino acids are rarely found in natural proteins. D-amino acids can be synthesized from the corresponding L-amino acids. The following synthetic scheme is one of the possible methods.

(a) Draw the structures of intermediates 1 and 2 in this scheme.

(b) How do we know that the product is entirely the unnatural D configuration?

4
views
Textbook Question

Metabolism of arginine produces urea and the rare amino acid ornithine. Ornithine has an isoelectric point close to 10. Propose a structure for ornithine.

1
views
Textbook Question

Use Figure 23-3 (the D family of aldoses) to name the following aldoses.

(d) the enantiomer of D-galactose

(e) the C5 epimer of D-glucose

4
views
Textbook Question

There are many methods for activating a carboxylic acid in preparation for coupling with an amine. The following method converts the acid to an N-hydroxysuccinimide (NHS) ester.

(a) Explain why an NHS ester is much more reactive than a simple alkyl ester.

1
views
Textbook Question

There are many methods for activating a carboxylic acid in preparation for coupling with an amine. The following method converts the acid to an N-hydroxysuccinimide (NHS) ester.

(c) Propose a mechanism for the reaction of the NHS ester with an amine, R–NH2.

7
views
Textbook Question

Histidine is an important catalytic residue found at the active sites of many enzymes. In many cases, histidine appears to remove protons or to transfer protons from one location to another.

(a) Show which nitrogen atom of the histidine heterocycle is basic and which is not.

(b) Use resonance forms to show why the protonated form of histidine is a particularly stable cation.

(c) Show the structure that results when histidine accepts a proton on the basic nitrogen of the heterocycle and then is deprotonated on the other heterocyclic nitrogen. Explain how histidine might function as a pipeline to transfer protons between sites within an enzyme and its substrate.

1
views