Table of contents

1. A Review of General Chemistry5h 5m
2. Molecular Representations1h 14m
3. Acids and Bases2h 46m
4. Alkanes and Cycloalkanes4h 17m
5. Chirality3h 39m
6. Thermodynamics and Kinetics1h 22m
7. Substitution Reactions1h 48m
8. Elimination Reactions2h 30m
9. Alkenes and Alkynes2h 9m
10. Addition Reactions3h 19m
11. Radical Reactions1h 58m
12. Alcohols, Ethers, Epoxides and Thiols2h 42m
13. Alcohols and Carbonyl Compounds2h 17m
14. Synthetic Techniques1h 26m
15. Analytical Techniques:IR, NMR, Mass Spect7h 3m
16. Conjugated Systems6h 13m
17. Ultraviolet Spectroscopy51m
18. Aromaticity2h 34m
19. Reactions of Aromatics: EAS and Beyond5h 1m
20. Phenols55m
21. Aldehydes and Ketones: Nucleophilic Addition4h 56m
22. Carboxylic Acid Derivatives: NAS2h 51m
23. The Chemistry of Thioesters, Phophate Ester and Phosphate Anhydrides1h 10m
24. Enolate Chemistry: Reactions at the Alpha-Carbon1h 53m
25. Condensation Chemistry2h 9m
26. Amines1h 43m
27. Heterocycles2h 0m
28. Carbohydrates5h 53m
29. Amino Acids4h 20m
30. Peptides and Proteins2h 42m
31. Catalysis in Organic Reactions1h 30m
32. Lipids 2h 50m
33. The Organic Chemistry of Metabolic Pathways2h 52m
34. Nucleic Acids1h 32m
35. Transition Metals6h 14m
36. Synthetic Polymers1h 49m

22. Carboxylic Acid Derivatives: NAS

Nucleophilic Acyl Substitution

Organic Chemistry

22. Carboxylic Acid Derivatives: NAS

Nucleophilic Acyl Substitution

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5:49 minutes

Problem 45c

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.

Verified step by step guidance

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.

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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.

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.

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.

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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.

Key Concepts

Carboxylic Acid Derivatives

Nucleophilic Acyl Substitution

Mechanism of Amine Reactions

Watch next

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.