EXPERIMENTACIÓN Avanzada en Química Orgánica – 3º Grado Química - ULL
Multistep Synthesis
The Grignard reaction and the addition of protecting groups are standard reactions in organic chemistry.
The multistep synthesis of 4,4-diphenyl-3-buten-2-one from ethyl acetoacetate includes these reactions.
Ethyl acetoacetate, a -ketoester, undergoes protection with ethylene glycol to provide an acetal ester.
The acetal ester is then treated with phenylmagnesium bromide, which is prepared prior to use, followed
by an aqueous acid quench to produce a tertiary alcohol that can be purified by recrystallization. Finally,
the acetal is removed, and the tertiary alcohol undergoes dehydration under acid-catalyzed conditions to
provide 4,4-diphenyl-3-buten-2-one. Characterization of products at each stage of the synthesis can be
done by using 1H NMR spectroscopy. The experiment teaches not only about classic reactions in organic
chemistry, but also the difference between quench and hydrolysis steps.
Synthesis of ethyl acetoacetate ethylene ketal
To a 500 ml round bottom flask equipped with a reflux condenser and Dean-Stark water
separator is added 30 g of ethyl acetoacetate, 15 g of ethylene glycol, 130 mg of p-
toluenesulfonic acid monohydrate, and 100 mL of toluene.
The resulting solution is refluxed until the theoretical amount of water is removed (4.2 mL,
1 hr).
The reaction mixture is cooled to room temperature and washed with 50 mL of 10%
sodium hydroxide, two 50-mL portions of water, and dried over anhydrous potassium
carbonate.
After filtration the toluene is removed by vacuum rotavap. The crude ethylene ketal
product was purified by means of a vacuum distillation to give ketal (b.p. 135-138°C at 50
mm).
• Weigh the product and calculate the reaction yield.
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EXPERIMENTACIÓN Avanzada en Química Orgánica – 3º Grado Química - ULL
Synthesis of 2-(2-methyl-1,3-dioxolan-2-yl)-1,1-diphenylethan-1-ol
*Scaled up or down as necessary
All of the glassware required for this experiment should be dried in an oven overnight,
and should be assembled while it was still hot. Drying tube is added to the top of the
apparatus to seal the system from moisture.
To a 500 ml overnight-dried round bottom flask equipped with a reflux condenser,
addition funnel, a magnetic stirring bar and a calcium chloride drying tube placed an top of the condenser
is added 5.35 g (0.22 g-atom) of magnesium turnings, 30 ml of anhydrous ethyl ether and a crystal of
iodine. A solution of 31.4 g (0.2 mol) of bromobenzene in 50 ml of anhydrous ether is added dropwise,
through the addition funnel, with stirring at such a rate as to maintain a steady reflux. After the addition is
complete the mixture is refluxed for 25 min, cooled in an ice-bath and then a solution of 17.4 g (0.10 mol)
of the ketal-ester in 50 ml of anhydrous ether is added dropwise with stirring. After addition is complete,
the reaction mixture is stirred at room temperature for 30 min.
Then a mixture of 50 ml of water and 50 g of ice is added to the reaction flask. When the ice has melted,
50 ml of ether is added and the mixture stirred until the gummy residue dissolves.
The layers are separated and the water layer washed with 50 ml of ether. The combined ether portions
are washed with 50 ml of water and dried over anhydrous magnesium sulfate. The ether is removed by
vacuum rotavap to give an orange liquid that crystallizes upon cooling.
The crude product is recrystallized from n-hexane (60-90ºC) to give pure ketal-alcohol. m.p. 90-91ºC
• Weigh the product and calculate the reaction yield.
Synthesis of 4,4-diphenyl-3-buten-2-one
*Scaled up or down as necessary
M.M.Afonso 2
EXPERIMENTACIÓN Avanzada en Química Orgánica – 3º Grado Química - ULL
To 10 g of the keto-alcohol in a 250 ml round bottom flask, is added 2.5 ml of concentrated HCl, 100 ml of
acetone and 4.5 ml of water. The mixture is refluxed one hour, diluted with 100 ml of water, and extracted
with two 50 ml portions of ether. The combined ether extracts are washed with 50 ml of saturated sodium
bicarbonate and 50 ml of water and dried over anhydrous magnesium sulfate. After filtration the solvent is
removed by evaporation to give crude 4,4-diphenyl-3-buten-2-one.
• Weigh the crude product and calculate the reaction yield.
A sample of the crude product (1.5 g) can be purified by column chromatography over silica gel.
The intermediate hydroxyketone
Synthesis of 4-hydroxy-4,4-diphenyl-3-butan-2-one
*Scaled up or down as necessary
The hydrolysis of the hydroxyketal may be done with isolation of the intermediate hydroxyketone. If
dilute acid is used 4-hydroxy-4,4-diphenylbutan-2-one can be obtained in excellent yield.
Experimental: A mixture of 1 g, best recrystallized from ethanol, and 0.02 M HCI (20 ml, prepared
from 1.0 ml 1 M HCl, 5 ml H2O and 50 ml acetone) is refluxed for 15 min, cooled, poured into a solution of
saturated sodium bicarbonate (10ml) and water (10 ml), and extracted with ether (2 X 50 ml). The
combined ether extracts are washed with water, dried over calcium chloride and evaporated to give 4-
hydroxy-4,4-diphenyl-3-butan-2-one. Recrystallization from hexane affords pure compound.
Pre-Lab Questions:
1. Write each of the mechanisms involved in every stage.
2. Why is it necessary to use a Dean-Stark in the first step of the synthesis?
3. Why two phenyl residues are added to the ester?
4. Can you suggest a synthesis of 4,4-diphenylbut-3-en-2-one without using Grignard synthesis?
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EXPERIMENTACIÓN Avanzada en Química Orgánica – 3º Grado Química - ULL
5. Why do you have to take precautions to prevent the presence of moisture in the preparation of the
Grignard reagent?
6. Create a table of physical constants and safety data for all chemicals and solutions referred to in the
experiment. Reference any sources.
7. Which are the differences between quench and hydrolysis steps?
Post-Lab Report
M.M.Afonso 4
