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 45c
Chapter 24, Problem 45c

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

Verified step by step guidance
1
Step 1: Recognize the functional groups involved in the reaction. The NHS ester contains an activated ester group, which is highly reactive toward nucleophiles like amines due to the electron-withdrawing properties of the succinimide ring.
Step 2: Identify the nucleophile in the reaction. The amine (R-NH2) acts as the nucleophile, attacking the carbonyl carbon of the NHS ester. This occurs because the carbonyl carbon is electrophilic, making it susceptible to nucleophilic attack.
Step 3: Propose the first step of the mechanism. The lone pair of electrons on the nitrogen atom of the amine attacks the carbonyl carbon of the NHS ester, forming a tetrahedral intermediate. This intermediate is stabilized by the resonance of the succinimide ring.
Step 4: Describe the collapse of the tetrahedral intermediate. The intermediate undergoes rearrangement, leading to the expulsion of the N-hydroxysuccinimide (NHS) group as a leaving group. This step regenerates the carbonyl group and forms the amide bond between the carboxylic acid derivative and the amine.
Step 5: Conclude the reaction. The final product is an amide (R-CONH-R') formed from the coupling of the NHS ester and the amine, along with the release of NHS as a byproduct. This reaction is efficient due to the excellent leaving group properties of NHS.

Verified video answer for a similar problem:

This video solution was recommended by our tutors as helpful for the problem above.
Video duration:
5m
Was this helpful?

Key Concepts

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

Carboxylic Acid Derivatives

Carboxylic acids can form various derivatives, such as esters and amides, which are more reactive than the parent acid. The conversion of a carboxylic acid to an N-hydroxysuccinimide (NHS) ester is a common method to enhance its reactivity towards nucleophiles, like amines. Understanding these derivatives is crucial for predicting reaction mechanisms and outcomes.
Recommended video:
Guided course
03:50
Intro to Carboxylic Acid Derivatives

Nucleophilic Acyl Substitution

Nucleophilic acyl substitution is a fundamental reaction mechanism in organic chemistry where a nucleophile attacks the carbonyl carbon of an acyl compound, leading to the replacement of a leaving group. In the case of the NHS ester reacting with an amine, the amine acts as the nucleophile, attacking the carbonyl carbon and forming a new amide bond while releasing NHS as a leaving group.
Recommended video:
Guided course
01:47
Nucleophiles and Electrophiles can react in Substitution Reactions.

Mechanism of Amine Reactions

The mechanism of amine reactions involves the formation of a tetrahedral intermediate when the amine nucleophile attacks the carbonyl carbon. This intermediate can then collapse, leading to the formation of a new bond and the expulsion of a leaving group. Understanding this mechanism is essential for predicting the products and the steps involved in the reaction of NHS esters with amines.
Recommended video:
Guided course
03:46
Buchwald-Hartwig Amination Reaction
Related Practice
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.

(b) Propose a mechanism for the reaction shown.

462
views
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?

648
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.

1499
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

612
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.

649
views