CHM271 Exam 3 Spring 2022 Comprehensive Study Notes

Carbonyl Naming and Functional Group Identification

• Amide Nomenclature:     * Substituents on the Nitrogen are indicated by the prefix "N-".     * The longest carbon chain containing the carbonyl carbon determines the parent name.     * Example from structure 4: The correct IUPAC name is N,3-dimethylpentanamide.

• Ester Nomenclature:     * The alkyl group attached to the oxygen is named first (from the alcohol part).     * The acyl part (acid side) is named as the parent carboxylate with the suffix "-oate".     * Example from structure 5: A structure with a five-carbon acyl chain and an ethyl group on the oxygen is named ethyl pentanoate.

• Functional Group Identification:     * Correct identification of functional groups is essential for organic synthesis and naming. In question 18, it is noted that specific groups II, III, and V were correctly named.

Enolate Chemistry and Alpha-Substitution Reactions

• Enolate Formation and Steric Hindrance:     * Lithium diisopropylamide ($LDA$) is a strong, hindered base used to generate kinetic enolates from ketones like cyclohexanone.     * A synthesis attempt (Question 1) using cyclohexanone, $LDA$, and 2-methyl-2-bromopentane fails because the tertiary bromide is too sterically hindered for a nucleophilic attack by the enolate (an $S_{N}2$ reaction mechanism).

• Alpha-Halogenation of Ketones:     * Ketones can undergo halogenation at the alpha-position.     * In the presence of an acid catalyst ($H_{3}O^{+}$) and bromine ($Br_{2}$), a ketone such as 1-phenyl-2-butanone will substitute a hydrogen at the alpha-position with a bromine atom. The major product in Question 3 is the alpha-brominated structure (A).

• Acidity of Protons:     * Protons positioned between two electron-withdrawing groups (such as carbonyls) are significantly more acidic than regular alkanes or lone alpha-protons.     * In a dicarbonyl system (Question 28), the hydrogen labeled at position 3 is the most acidic because its conjugate base (enolate) is stabilized by resonance with both carbonyl groups.

• The Iodoform Test:     * This test is used to detect the presence of methyl ketones ($CH_{3}C=O$).     * Reaction with iodine and base results in the formation of a yellow precipitate of iodoform ($CHI_{3}$).     * Among the compounds listed in Question 23, 2-pentanone gives a positive iodoform test because it possesses a methyl group directly attached to the carbonyl carbon. 3-pentanone, benzophenone, and cyclohexanone do not contain this specific methyl ketone moiety.

Aldol and Claisen Condensations

• General Mechanisms:     * Aldol Addition/Condensation: Involves the nucleophilic attack of an enolate onto the carbonyl of an aldehyde or ketone.     * Claisen Condensation: Involves the nucleophilic attack of an ester enolate on another ester, resulting in a beta-keto ester.

• Crossing Aldol Reactions:     * When acetone and ethanal ($CH_{3}CHO$) are mixed in base (Question 7), up to four possible aldol products can form: two from self-condensation (acetone-acetone and ethanal-ethanal) and two from crossed-condensation (acetone acting as nucleophile/ethanal as electrophile, and vice versa).

• Base Selection for Claisen Condensation:     * To avoid transesterification or unintended side reactions, the base used should match the alkoxide portion of the ester.     * For propyl ethanoate, the most appropriate base for promoting a self-Claisen condensation is sodium propoxide ($NaOCH_{2}CH_{2}CH_{3}$, Question 16).

• Dehydration of Aldol Products:     * Aldol products (beta-hydroxy carbonyls) often undergo dehydration to form alpha,beta-unsaturated carbonyl compounds.     * Question 24: Dehydration following an aldol condensation can result in 4-methyl-3-penten-2-one.

• Aldol Limitations:     * An aldehyde cannot undergo an aldol addition if it lacks alpha-hydrogens, as it cannot form an enolate. In Question 21, structure I is identified as an aldehyde that does NOT undergo aldol addition.

Nucleophilic Acyl Substitution and Carboxylic Acid Derivatives

• Mechanism of Nucleophilic Acyl Substitution:     * The reaction proceeds via a two-step mechanism: addition of a nucleophile to the carbonyl carbon to form a tetrahedral intermediate, followed by the loss of the leaving group (Question 8).     * The identity of the nucleophile dictates the type of functional group in the final product (Question 15).

• Reactivity and Synthesis of Derivatives:     * Acid Chlorides: High reactivity makes them excellent starting materials. To synthesize an anhydride from an acid chloride, a carboxylic acid is selected as the nucleophile (Question 9).     * Hydrolysis Rates: The rate of hydrolysis in aqueous $NaOH$ depends on the leaving group ability and steric factors. Amides typically undergo hydrolysis more slowly than esters or acid halides (Question 22).

• Sequential Reactions from Esters:     * Starting with ethyl benzoate (Question 19):         1. Reaction with aqueous dilute acid ($H_{3}O^{+}$) and heat hydrolyzes the ester to benzoic acid.         2. Reaction with thionyl chloride ($SOCl_{2}$) converts the acid into benzoyl chloride.         3. Reaction with ethylamine ($CH_{3}CH_{2}NH_{2}$) converts the acid chloride into an amide: N-ethylbenzamide.

• Acid-Catalyzed Esterification (Fischer Esterification):     * The mechanism involves protonation of the carbonyl oxygen, followed by nucleophilic attack of an alcohol (e.g., methanol) to form a tetrahedral intermediate (Question 30).

Reduction and Multi-Step Synthesis Strategies

• Reduction Reagents:     * Lithium Aluminum Hydride ($LiAlH_{4}$ or LABH): A powerful reducing agent capable of reducing esters, carboxylic acids, and amides to alcohols or amines (Question 31).     * Sodium Borohydride ($NaBH_{4}$): A milder reducing agent typically used for aldehydes and ketones, often in methanol ($CH_{3}OH$).     * DIBAL-H: Often used for the partial reduction of esters to aldehydes at low temperatures.

• Malonic Ester Synthesis:     * Used to synthesize substituted acetic acids. A step involves the alkylation of a malonic ester enolate with an alkyl bromide. Question 27 asks for the appropriate alkyl bromide for a specific carboxylic acid product, identified as structure V.

• Acetoacetic Ester Synthesis Sequence:     * A typical three-step sequence (Question 26) involves:         1. Deprotonation by base ($CH_{3}CH_{2}O^{-}$).         2. Alkylation (e.g., with $CH_{3}CH_{2}CH_{2}Br$).         3. Hydrolysis and decarboxylation ($HCl, H_{2}O, \text{heat}$).     * The product is a substituted ketone.

CHM271 Exam 3 Spring 2022 Answer Key

1. D: Tertiary bromide steric hindrance.

2. B: Major product of ester/aldehyde reaction.

3. A: Alpha-brominated ketone.

4. E: N,3-dimethylpentanamide.

5. C: Ethyl pentanoate.

6. A: Major product of unlabeled reaction (A-4).

7. E: 4 possible aldol products.

8. C: Addition-elimination mechanism.

9. A: Carboxylic acid to form anhydride.

10. B: Self-aldol product II.

11. D: Claisen product IV.

12. A: Major organic product I.

13. E: Claisen product V.

14. B: Starting materials II.

15. B: Nucleophile determines product functional group.

16. D: Sodium propoxide ($NaOCH_{2}CH_{2}CH_{3}$).

17. B: II and III.

18. C: II, III, and V correctly named.

19. B: Product b (N-ethylbenzamide).

20. D: Product d.

21. A: Structure I (No aldol addition).

22. B: Compound hydrolyzed most slowly.

23. B: 2-pentanone (positive iodoform).

24. A: 4-methyl-3-penten-2-one.

25. A: Reactant set A.

26. C: Major product C.

27. E: Alkyl bromide V.

28. C: Hydrogen atom 3.

29. C: Major organic product 3.

30. C: Mechanism step C.

31. A: LAH reduction product I.

32. C: Sequence product 3.

33. D: $LiAlH_{4}$ then $H_{2}O$.

1. Nucleophilic Acyl Substitution:     - Reaction of nucleophiles with acyl compounds (e.g., esters, amides) leading to the substitution of the acyl group.

2. Aldol Condensation:     - Involves the nucleophilic attack of an enolate on a carbonyl compound, followed by dehydration to form α,β-unsaturated carbonyls.

3. Claisen Condensation:     - Reaction between two esters or an ester and a carbonyl compound, forming a β-keto ester.

4. Enolate Chemistry:     - Includes reactions like alpha-halogenation and enolate formation using strong bases (e.g., $LDA$).

5. Esterification (Fischer Esterification):     - Formation of esters from carboxylic acids and alcohols in the presence of an acid catalyst.

6. Reduction Reactions:     - Reduction of carbonyl compounds (e.g., ketones and aldehydes) using reducing agents (e.g., $NaBH_4$, $LiAlH_4$).

7. Iodoform Test:     - Identification of methyl ketones via reaction with iodine and base leading to the formation of iodoform.

8. Decarboxylation:     - Loss of a carboxyl group as carbon dioxide from carboxylic acids, typically leading to an alkane or an unsaturated compound.

9. Hydrolysis Reactions:     - Reaction of esters and amides with water leading to the formation of acids (or alcohols and amines for amides).

10. Diels-Alder Reaction:      - A cycloaddition reaction between a diene and a dienophile, forming a cyclic compound.