Michael Addition (What is the mechanism of the Michael Addition?)

ChemActivity 37 ChemActivity Michael Addition Reaction 1 37 Michael Addition (What is the mechanism of the Michael Addition?) Model 1: 1,4 vs 1,...
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ChemActivity 37

ChemActivity

Michael Addition Reaction

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37 Michael Addition

(What is the mechanism of the Michael Addition?)

Model 1: 1,4 vs 1,2 Addition to an α,β-Unsaturated Carbonyl The common carbon nucleophiles we have studied so far (Li and Grignard reagents) “prefer” to add to the 2-position because… • the 1,2-addition is faster than the 1,4-addition and • it is very downhill to the right so as to be irreversible. Grignard & Li nucleophiles

1,2-Add'n 1,4-Add'n

Critical Thinking Questions 1. One of the following synthetic targets is not easily accessible from the starting material using Grignard or lithium nucleophiles. a) b)

Indicate the new C-C sigma bond in each Target. Cross out the more inaccessible target and explain your reasoning.

Target B is hard to make using a Grignard or lithium reagent since it requires a 1,4 addition. CH(CH3)2

Target A OH

O

CH(CH3)2

Starting Material Target B O

c)

T or F: Using reactions we have studied, C-C bond formation at the 4position of an α,β-unsaturated carbonyl compound is difficult or impossible, while C-C bond formation at the 2-position is easy.

ChemActivity 37

Michael Addition Reaction

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Model 2: Michael Addition Reaction Professor Arthur Michael (1853-1942) of Harvard University developed a method for making carbon-carbon sigma bonds at the 4-position of an α,β-unsaturated carbonyl compound. The reaction now bears his name. N O

O

H

O

C

C

C

C

O

O

(catalyst)

C H

H H

C H

pyridine

C

C

H

C

H

H

H

H

H2C

Michael Addition Product

Phenyl Group abreviated "-Ph"

4-pos.

CH2

C

O

Ph

Critical Thinking Questions 2. Indicate the new C-C sigma bond in the reaction above. 3. On the product, indicate the carbon that was originally the 4-position (or β-position) of the α,β-unsaturated carbonyl compound. 4. What does the Michael Reaction accomplish that cannot be done with other reactions we have studied? Carbon-carbon bond formation at the 4 position of a α,β-unsaturated carbonyl compound

5. Pyridine is a moderate base and a poor nucleophile. a) Use curved arrows to show the most likely acid-base reaction (proton transfer) involving pyridine and one of the reactants in Model 2. O C H

H

O

C

C H H

C H

O

C C

H

N

O

O

C

Ph

pyridine

C

H

H

H

O

C

C

C

O

C

C

H

C

H

C

H

H

H

O

O

H

b) Draw the conjugate base, including all important resonance structures. c) Explain why the proton you pulled off with pyridine is the most acidic proton among those on the reactant molecules. 6. Use curved arrows to show a mechanism for the Michael Addition in Model 2. O

O

C H

O

C C

C

H H

H H C H

H

H N

HC C

Ph Ph

H

H CH2

C C

O

C

C C

H O

O

O

O

C C

H

C H

CH2

C H

H CH2

H2C C

Ph

C

H

tautomerize

HC

O

O

OH

C Ph

O

H

ChemActivity 37

Michael Addition Reaction

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Exercises 1. Can the 1,2-addition product shown in Model 1 tautomerize to a lower energy keto form? Explain. 2. The 2nd order resonance structure below explains why the carbonyl carbon is electrophilic and the carbonyl oxygen is nucleophilic. δ O O O O C

C

H3C

H very bad resonanc structure (O must have an octet)

C

H3C

H

H3C

= H

δC H3C

H

composite structure

Draw similar resonance structures for the α,β-unsaturated aldehyde below. O

H Cβ H3C

C Cα

H

H

a) Complete the following composite structure for this aldehyde by adding δ + and δ – where necessary. [A composite structure uses partial charges (δ +) and partial bonds (---) to represent multiple resonance structures at the same time.] H

O

Cβ H3C

C Cα

H

H

b) Is the β-carbon of an α,β-unsaturated carbonyl compound electrophilic or nucleophilic [circle one]? c) Based on the pattern of charge distribution on the α,β-unsaturated aldehyde above, do you expect the α-carbon to have a δ + or δ – charge [circle one]? d) Is the α-carbon of an α,β-unsaturated carbonyl compound electrophilic or nucleophilic [circle one]? 3. For each of the following reactions… i) Identify each α-carbon that will act as a nucleophile and whether it will be an enol or an enolate nucleophile. ii) Identify each β-carbon that will act as an electrophile iii) Identify each carbonyl carbon that will act as an electrophile. iv) Draw the keto form of any enol product shown. v) Identify each 1,2-addition and each 1,4-addtion (some are neither).

ChemActivity 37

Michael Addition Reaction

O O H

N (LDA)

C Cα

H

H

H Li

δ H2C R

H

C Cα

H

H

Br δ

CH2

R

O H

N (LDA)

C Cα

H

Li

H Br

H

O

Br

H

H O H

OH



H

H

δ 1) H2C

H

H H

O



C Cα

δ Li



H H H O



2) neutralize with dilute HCl/H2O

C Cα

H3C

H CH2

H

R

H

O



C

H tautomerize

HCl H



H3C

H

Cl

H

H

H

O



C Cα

H3C

C

C

H

R

C Cα

H3C

O

H O

Cβ H3C

Br

H3C

H H

H

OH

C

H

C Cα

OH

O



C

H tautomerize

H2O

H

H



H3C

H

OH

H

H

4. The di-ketone below can undergo an intramolecular Michael Addition. Draw the mechanism of this reaction. O

O

K

OH

4

ChemActivity 37

Michael Addition Reaction

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5. The reactants from the Michael Reaction in Model 2 are drawn below. Describe reaction conditions that would minimize the formation of the aldol product shown below. O C H

H

O

C

C

H

O

C

H H

C

N

O

C

H

O

C Ph

C

H

pyridine

C H

H

H CH

OH

H2C

Not Involved in Aldol Aldol Product

C

O

H

6. H2NNH2 in base selectively reduces an aldehyde C=O to a CH2. (At higher temperatures it can reduce a ketone C=O to a CH2.) O

H

H

H2NNH2, KOH C R

C R'

R

R'

Design a synthesis of Target B in CTQ 1 from the starting material shown there.

7. Show the mechanism of each reaction in Exercise 3. 8. Design an efficient synthesis of each of the following target molecules. All carbon atoms must come from the starting material/s given. O O

O O H

Target

Ph

Ph

Ph

O

OH

H

Ph O

C Starting material

CH

O

C

Br

O

Hint: consider Markov. & Hint: this synthesis involves a Anti-Markov. hydration Grignard reagent in one step and ozone in another.

9. Read the assigned pages in the text and do the assigned problems.

Ph

C

Use any of the starting materials OR PRODUCTS listed so far on this table.

ChemActivity 37

Michael Addition Reaction

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