ORGANIC - BRUICE 8E CH CARBONYL COMPOUNDS III: REACTIONS AT THE ALPHA-CARBON

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2 CNCEPT: ALPHA CARBNS AND TAUTMERIZATIN We have discussed the high reactivity of the carbonyl carbon. However, carbonyls contain another highly reactive component. What is the acidity of the β-carbon? What is the acidity of the α-carbon? Which phenomenon is responsible for this difference? Tautomerization General Reaction: Acid-Catalyzed Mechanism: Base-Catalyzed Mechanism: Page 2

3 PRACTICE: Draw the enol tautomer for the following compound. Cyclopentanone Page 3

4 CNCEPT: ENLATES Upon deprotonation, the α-carbon forms a resonance-stabilized intermediate structure called an Both notations can be used to represent an enolate Note that the negative charge now rests on the This makes the α-carbon of the enolate a good General Reactions of Enolates: Page 4

5 CNCEPT: ELECTRPHILIC α-halgenatins Acid-Catalyzed α-halogenation: Always yields -halogenation PRACTICE: Provide the major product for the following reaction. Br 2 CH 3 H + Page 5

6 CNCEPT: ELECTRPHILIC α-halgenatins Base-Catalyzed α-halogenation: May yield -halogenation PRACTICE: Provide the major product for the following reaction. Br 2 excess NaH Page 6

7 CNCEPT: ELECTRPHILIC α-halgenatins The Haloform Reaction: Base-Catalyzed α-halogenation of The α-carbon is transformed into a good through successive halogenations. PRACTICE: Provide the major product for the following reaction. Br 2 excess NaH Page 7

8 CNCEPT: ELECTRPHILIC α-halgenatins The HVZ Reaction PRACTICE: Provide the major product after each step for the following reaction. Br 2, PBr 3 NH 3 H H 2 Page 8

9 CNCEPT: VERVIEW F α-carbn ALKYLATINS AND ACYLATINS Adding R groups to α-carbons of carbonyl compounds is synthetically important. There are main synthetic pathways that we use to accomplish this. Page 9

10 CNCEPT: ENLATE ALKYLATIN AND ACYLATIN We can expose enolates to alkyl halides to produce α-alkyations Using acid chlorides results in α-acylations. Directed Reactions: When we run α-alkyations with asymmetrical ketones, two enolates are possible. This leads to a mixture of products. We can use different bases to direct the direction of deprotonation The thermodynamic product is the product with the lowest overall energy The kinetic product is the product with the lowest activation energy Enolates of Esters: LDA can also be used in the alkylation of esters Use of alkoxide bases may yield transesterification (stay away!) Page 10

11 PRACTICE: The following molecule forms two products. Determine the products and determine if they follow thermodynamic control or kinetic control. 1) TBuK, TBuH 2) CH 3 Br 1) LiH 2) CH 3 Br Page 11

12 CNCEPT: ENAMINE ALKYLATIN AND ACYLATIN Carbonyls easily react with acid-catalyzed amine solvents to form imines and enamines. Secondary Amine Addition: Enamines Enamines have the ability to alkylate or acylate via the formation of an iminium salt EXAMPLE: Predict the products of the following reactions 1. Page 12

13 PRACTICE: Provide the major product after each step for the following reaction. H N Br H 3 + H + Acetone PRACTICE: Which of the following can NT be formed through the stork enamine reaction with 2-butanone? a) 3-pentanone b) 3-methyl-2-butanone c) 2-octanone d) 3-octanone Page 13

14 CNCEPT: TAUTMERS F DICARBNYL CMPUNDS Most carbonyl compounds favor the tautomer β-dicarbonyl compounds favor the tautomer due to and β-dicarbonyl compounds are exceptionally acidic due to the high stability of the conjugate base If the α-carbon exists as a chiral center, that carbon will ALWAYS BE EXAMPLE: Which of the following ketones is the most acidic? Page 14

15 CNCEPT: β-dicarbnyl ESTER SYNTHESIS PATHWAY β-dicarbonyl compounds are unusually acidic due to the incredible stability of the enolate. We can take advantage of this acidity to easily alkylate the central α-carbon through a predictable multi-step synthesis. β-dicarbonyl Ester Synthetic Pathway Page 15

16 CNCEPT: ACETACETIC ESTER SYNTHESIS GENERAL REACTINS EXAMPLE: Predict the products of the following multi-step reactions Page 16

17 PRACTICE: Provide the major product for the following reaction H 3 C CH 3 1. NaEt 2. PhCH 2 Br 3. H Δ PRACTICE: Beginning from ethyl acetoacetate, and using any other necessary reagents, show the necessary compounds needed to form the following compound. Page 17

18 CNCEPT: MALNIC ESTER SYNTHESIS GENERAL REACTINS EXAMPLE: Predict the products of the following multi-step reactions Page 18

19 PRACTICE: Provide the major product for the following reaction 1. 2 moles NaEt, EtH 2. BrCH 2 CH 2 CH 2 Br H 3 C CH 3 3. NaH, H 2, H LiAlH 4 PRACTICE: Provide the major product for the following reaction 1. NaEt, EtH 2. CH 3 CH 2 CH 2 Br H 3 C CH 3 3. NaH, H 2, H Heat PRACTICE: Beginning from diethyl malonate, and using any other necessary reagents, show the necessary compounds needed to form the following compound. H Page 19

20 CNCEPT: CNDENSATIN REACTINS A condensation reaction spontaneously combines two or more molecules with the loss of a smaller molecule. Instead of just reacting with electophiles, enolates are able to react with themselves to self-condensate bviously, are required for this type of reaction to take place Example Reactions: Page 20

21 CNCEPT: ALDL CNDENSATIN Via enolates, ketones and aldehydes will react with to condensate into The final products are called aldols because they are part and part Mechanism: 1. Form the enolate 2. Nucleophilic attack the other carbonyl (which we will call the electrophile) 3. Protonate the tetrahedral intermediate: β-hydroxy carbonyls are to dehydrate than typical alcohols due to Many times, we will simply assume that the condensation product dehydrated on its own, without requiring an explanation. Page 21

22 PRACTICE: What product can be isolated from the following aldol condensation reaction? H Page 22

23 PRACTICE: Provide the mechanism for the following transformation. H H H Page 23

24 CNCEPT: DIRECTED CNDENSATINS When we run condensation reactions with asymmetrical ketones, two enolates may be possible. We can use different bases to direct the direction of deprotonation The thermodynamic enolate is the substituted one. Favored by bases. The kinetic enolate is the substituted one. Favored by bases. EXAMPLE: Predict the products of the following self-condensation. Page 24

25 CNCEPT: CRSSED ALDL When we run condensation reactions on two different ketones or aldehydes, mixed products are difficult to avoid. In general, condensation reactions with two different carbonyls work best when one carbonyl is nonenolizable. Nonenolizable Carbonyls: Page 25

26 PRACTICE: Give the structure of the aldehydes or ketones used to create the product prepared by a crossed aldol condensation reaction. PRACTICE: Give the structure of the aldehydes or ketones used to create the product prepared by a crossed aldol reaction. H PRACTICE: What product can be isolated from the following aldol condensation reaction? H H Page 26

27 CNCEPT: CLAISEN-SCHMIDT REACTIN When a crossed aldol contains an enolizable aldehyde and a ketone, one product does predominate. Aldehydes are more susceptible toward nucleophilic addition than ketones, favoring a single enolate. EXAMPLE: Predict the major product of the following condensation. Page 27

28 CNCEPT: CLAISEN CNDENSATIN Via enolates, esters will react with to condensate into Mechanism: 1. Form the enolate 2. Nucleophilic attack the other carbonyl (which we will call the electrophile) 3. Kick out the good leaving group: Example Application: Page 28

29 PRACTICE: Draw the structure of the Claisen condensation product for each of the following compounds. NaEt Et Et EtH PRACTICE: Draw the structure of the Claisen condensation product for each of the following compounds. NaMe MeH PRACTICE: Give the structure of the ester precursor for the following Claisen condensation product. Page 29

30 CNCEPT: INTRAMLECULAR CNDENSATIN Dicarbonyl compounds have the ability to self-condensate through cyclization if it will generate a or -membered ring. When a diketone or dialdehyde self-condensate, the resulting product is called a cyclic enone When a diester self-condensates, the resulting product is called a cyclic β-ketoester This is known as a Dieckmann Condensation Page 30

31 PRACTICE: Consider the following reaction. Provide a stepwise mechanism to explain the given transformation. Page 31

32 CNCEPT: CNJUGATE ADDITIN F ENNES nce an aldol condensation is completed, an electrophilic carbonyl still remains. Enones remain susceptible to nucleophilic attack, however they now have two electrophilic regions: Also known as 1,2 vs. 1,4 addition of enones, or nucleophilic addition vs. conjugate addition of carbonyls. Nucleophilic Addition vs. Conjugate Addition Page 32

33 CNCEPT: THE MICHAEL REACTIN The Michael Reaction is a 1,4-conjugate addition of an enone with an enolate. Basically Always forms 1,5-dicarbonyls Mechanism: Page 33

34 PRACTICE: Determine the product in the following conjugated addition reaction. PRACTICE: Determine the product in the following conjugated addition reaction. PRACTICE: Determine the product in the following conjugated addition reaction. Page 34

35 CNCEPT: RBINSN ANNULATIN 1,5-dicarbonyl compounds have the ability to undergo intramolecular self-condensation into 6-membered enones. When the 1,5-dicarbonyl is generated via Michael Reaction (enone + enolate), it is called a Robinson Annulation ` Basically EXAMPLE: Predict the major product of the following Robinson Annulation. Page 35

36 PRACTICE: Provide the product for the following Robinson Annulation Reaction. PRACTICE: How would you prepare the following compound using a Robinson annulation reaction between a di-ketone and an alpha, beta unsaturated ketone? PRACTICE: How would you prepare the following compound using a Robinson annulation reaction between a ketone and an alpha, beta unsaturated ketone? Page 36