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

Lactones, Lactams and Cyclization Reactions

Organic Chemistry

22. Carboxylic Acid Derivatives: NAS

Lactones, Lactams and Cyclization Reactions

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1:53 minutes

Problem 49f

Textbook Question

Propose mechanisms for the following reactions.
(f)

Verified step by step guidance

Step 1: Analyze the reactant and product structures. The reactant is an amino ester (contains an amine group and an ester functional group), and the product is a lactam (a cyclic amide). This suggests that the reaction involves intramolecular nucleophilic attack and cyclization.

Step 2: Identify the nucleophile and electrophile. The amine group (-NH2) in the reactant acts as the nucleophile, while the carbonyl carbon of the ester group is the electrophile. The lone pair on the nitrogen can attack the carbonyl carbon.

Step 3: Propose the mechanism for nucleophilic attack. The nitrogen's lone pair attacks the carbonyl carbon of the ester, forming a tetrahedral intermediate. This intermediate is stabilized by the oxygen atom of the ester group.

Step 4: Describe the elimination step. The tetrahedral intermediate undergoes elimination of the methoxy group (-OCH3), leading to the formation of the cyclic amide (lactam). This step involves breaking the C-O bond and forming the C-N bond.

Step 5: Confirm the final product. The reaction results in the formation of a six-membered lactam ring, which is consistent with the product shown in the image. The mechanism involves intramolecular cyclization and substitution.

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Key Concepts

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

Nucleophilic Acyl Substitution

Nucleophilic acyl substitution is a fundamental reaction mechanism in organic chemistry where a nucleophile attacks an electrophilic carbonyl carbon, leading to the substitution of a leaving group. In the context of the reaction shown, the amine acts as the nucleophile, attacking the carbonyl carbon of the ester, which facilitates the formation of a new bond and the release of an alcohol.

Lactam Formation

Lactams are cyclic amides formed from the reaction of an amine with a carbonyl compound, typically involving a ring closure. In this reaction, the nucleophilic attack by the amine on the carbonyl carbon of the ester leads to the formation of a cyclic structure, resulting in a lactam. Understanding the conditions that favor lactam formation, such as the stability of the cyclic structure, is crucial for predicting the outcome of the reaction.

Reaction Mechanism Steps

A reaction mechanism outlines the step-by-step process by which reactants are converted into products. For the transformation depicted, the mechanism would include the nucleophilic attack, the formation of a tetrahedral intermediate, and the subsequent elimination of the leaving group, leading to the formation of the lactam. Analyzing each step helps in understanding the overall reaction dynamics and the factors influencing the reaction pathway.

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Related Practice

Textbook Question

Show how you would accomplish the following synthetic transformations. You may use any necessary reagents.

(d) γ-aminobutyric acid → pyrrolidine

Textbook Question

Show how you would accomplish the following syntheses in good yields.

(e)

(f)

Textbook Question

Macrolide antibiotics all have large rings (macrocycle) in which an ester makes the ring; a cyclic ester is termed a lactone. One example is erythromycin A, first isolated from soil bacteria in the 1950s. Over time, some pathogenic bacteria have developed resistance to erythromycin by evolving an enzymatic mechanism to cleave the macrocycle at the ketone. To counter this resistance, chemists modified the erythromycin structure to replace the ketone with an amine that the bacteria could not detoxify. This modified antibiotic, azithromycin, trade name Zithromax®, is one of the most prescribed drugs in the world for respiratory infections.

(a) Identify the lactone group in each structure that merits the classification as macrolides.

(b) Two groups are circled. What type of functional group are they? Explain.

Textbook Question

When ethyl 4-hydroxybutyrate is heated in the presence of a trace of a basic catalyst (sodium acetate), one of the products is a lactone. Propose a mechanism for formation of this lactone.

Textbook Question

Show how you would add a Grignard reagent to an ester or a nitrile to synthesize

(b) heptan-4-ol.

Textbook Question

Explain this curious result. What does this reaction tell you about the relative reactivity of esters and ketones?

Textbook Question

Macrolide antibiotics, including erythromycin and azithromycin (Zithromax®), contain a large ring lactone. One of the largest ever reported is Gargantulide A, the structure of which was determined by the research group of Prof. William Gerwick of the Scripps Institution of Oceanography (Organic Letters, 2015, 17, 1377–1380). Isolated from a Streptomyces bacterium, it kills pathogenic bacteria like MRSA and Clostridium difficile, but it proved too toxic to the test animals to continue further testing.

(a) Identify the lactone that makes this a macrolide structure.

(b) How many rings does this structure contain? How many atoms are in the largest ring?

Multiple Choice

What is the name of a cyclic ester?

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