Aldol

CHEM 334L Organic Chemistry Laboratory Revision 1.0

The Aldol Condensation Preparation of 4-Methoxybenzalacetone In this experiment 4-Methoxybenzalacetone, obtained through an aldol condensation of 4-Methoxybenzaldehyde and Acetone, will be synthesized in a one pot reaction. O

O 4-Methoxybenzalacetone (trans) Addition of a small amount of dilute aqueous Sodium Hydroxide to Acetaldehyde at low temperature initiates the conversion of the aldehyde into the dimer Aldol (from aldehyde alcohol),or 3-Hydroxybutanal. This reaction dates from 1872 and was an outgrowth of studies by Charles Adolphe Wurtz on the chemistry of aldehydes. O

O +

H

CH3

H

OH

NaOH, H2O, 5ºC

O

H3C H 3-Hydroxybutanal

CH3

Acetaldehyde

Upon heating, Aldol dehydrates to give Crotonaldehyde, or trans-2-Butenal, an α,β -unsaturated aldehyde. OH

O

H3C H 3-Hydroxybutanal

∆

O H3C H trans-2-Butenal

This reaction is an example of the more general Aldol Condensation reaction.

[Historically] aldehydes and ketones proved very useful in synthesizing reactions because of the activating influence of the carbonyl group on nearby hydrogen atoms (alpha hydrogen). The potential reactivity of the hydrogen in malonic acid was suggested by van't Hoff in 1874.

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The activation of the alpha hydrogen by a carbonyl group had been encountered empirically before van't Hoff's speculation. Use of the aldol condensation resulted from Wurtz's studies of aldehydes … The aldol condensation proved to be a general reaction of aldehydes with some ketones, provided hydrogen is present on the alpha carbon atom. In Kiel, Ludwig Claisen extended its use in several directions; he considered aldehydes with aldehydes, ketones, and esters under alkaline conditions and obtained valuable compounds, among them acetoacetic ester. This latter, discovered by Guether in 1863, was very useful in synthetic work. The Development of Modern Chemistry Aaron J. Ihde 1984

The Aldol Condensation Reaction

As for Aldol itself: A synthesis of butadiene from which a rubber was prepared by polymerization, has been effected from aldol; the steps in the process are indicated by the following formulas: CH3CH(OH)CH2CHO

CH3CH(OH)CH2CH2OH CH3CHClCH2CH2Cl

CH2=CHCH=CH2

While this synthesis lacks industrial significance at present, it is of interest in that it makes it possible to synthesize the rubber from coal, through the preparation of calcium carbide, acetylene and acetaldehyde. These latter steps in the process have been put on an industrial basis. Organic Chemistry James F. Norris 1931

Beyond its synthetic usefulness in forming C=C double bonds, the aldol condensation reaction is important because of its occurrence in many biochemical reactions. For example, the splitting of Fructose 1,6-bisphosphate into Glyceraldehyde 3-phosphate and Dihydroxyacetone phosphate during the metabolic degradation of Glucose is nothing more than a reverse aldol condensation catalyzed by the enzyme Aldolase:

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Mechanistically, the aldol condensation reaction is a simple nucleophilic addition reaction between an enolate ion and a carbonyl group. The enolate is formed when the base present abstracts an α-Hydrogen from a carbonyl compound. This Hydrogen is particularly acidic because of the resonance stabilization of the resulting enolate; illustrated below for 2-Butanone.

This enolate nucleophilically attacks carbonyl groupings in the typical fashion, forming the aldol product. The use of ketones in an aldol condensation reaction is frequently problematic. Treatment of Acetone, a ketone, with base leads, as expected, to the formation of 4-hydroxy-4-methyl-2pentanone, but the conversion is poor because of an unfavorable equilibrium with starting material.

O

O H3C

CH3

H3C

Acetone 94%

OH

NaOH, H2O, 5ºC

+ CH3

O

H 3C

CH3 CH3 3-Hydroxy-4-methyl-2-pentanone 6%

The lesser driving force of the aldol reaction of ketones is due to the greater stability of a ketone than an aldehyde. As a result, the aldol addition of ketones is endothermic. To drive the reaction forward, you can extract the product continuously from the reaction mixture as it is formed. Alternatively, under more vigorous conditions, dehydration and removal of water move the equilibrium toward the α,β-unsaturated ketone:

Benzalacetones are prepared via a mixed aldol condensation by the reaction of a substituted benzaldehyde with excess Acetone in aqueous base. Mixed aldol condensations typically form a mixture of products. However, in this case, because the benzaldehyde cannot form an enolate, and because Acetone is symmetric, only a single product is possible.

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H

O O

R

O +

A substituted benzaldehyde

H3C

OHCH3

Acetone

R

CH3 A benzalacetone (trans)

In our synthesis, we will start with the benzaldehyde p-Anisaldeyde and convert it to 4-Methoxybenzalacetone via an aldol condensation.

p-Anisaldehyde

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Pre-Lab Questions 1.

Give a mechanism for the preparation of 4-methoxybenzalacetone.

2.

Draw the structure of the cis and trans isomers of 4-methoxybenzalacetone. Why do we obtain the trans isomer?

3.

Using proton NMR, how could you experimentally determine that you have the trans isomer rather than the cis one? (Hint: Consider the use of coupling constants for the vinyl hydrogens.)

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Procedure Synthesis of 4-methoxybenzalacetone 1.

Dissolve 0.01 mole of anisaldehyde (4-methoxybenzaldehyde) in 10 mL of acetone in a 50-mL Erlenmeyer flask.

2.

In a separate 50-mL Erlenmeyer flask, dissolve 0.6 g of sodium hydroxide (NaOH) in 1 mL of water.

Note: It may be necessary to warm these mixtures to dissolve the solids. If this is necessary, then the solutions should be cooled to room temperature before proceeding with the next step. 3.

Combine the contents of the two flasks by adding the aldehyde/acetone mixture to the alkaline (NaOH) solution.

4.

After the addition, swirl the mixture for several minutes and allow the reaction to proceed for 1.5 hours. Swirl the mixture every 10 to 15 minutes during this period. (You should follow the course of the reaction by TLC. What solvent would be useful in separating the reactant from product?)

5.

When the reaction is complete, place the flask in an ice bath for 3 to 5 minutes. Add 25 mL of ice cold water to the mixture and cool it for about 5 minutes. The precipitate should be broken into small pieces with a stirring rod.

6.

Collect the product on a small Buchner funnel and wash it with four 25-mL portions of water.

7.

Recrystallize the compound from a minimum amount of hot 95% ethanol in the usual way.

8.

Allow the solid to dry completely and weigh the compound.

Spectroscopy 1.

Obtain a NMR spectrum of the product. Consult with your laboratory instructor about how to do this.

2.

Assign all the NMR peaks in the spectrum.

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Post-Lab Questions 1.

When the amount of acetone is decreased significantly, the benzalacetone becomes contaminated with a side-product that has consumed 2 moles of aromatic aldehyde. What is its structure and why is it produced when the amount of acetone is decreased?

2.

Provide the starting materials needed to prepare the following compounds: