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Honors Cup Synthetic Proposal (250 II-W PM-W08)Section: 250

Group Members: Adrienne Cheng, Eric Chow, Hannah VanVels

Title: Synthesis of Raspberry Ketone

Introduction: We will be attempting to synthesize 4-(4-hydroxyphenyl)butan-2-one, also knownas raspberry ketone. Raspberry ketone is the primary aroma of red raspberries. It is oftenindustrially produced for perfumery, cosmetics, and food additives. Studies have also shown thatwhen given to mice in large doses, it can assist in preventing obesity.

Overall Reaction Scheme:

CH2OH

HO

R: MCPBA

R: HClS: DMF

CHO

HO

CHO

HO

Me2CO

C: NaOH S: H2O

R: AcOH

O

CH3

HO

O

CH3

HO

CH2CH2COMe

HO

R: Zn, CH3COOH

4-(4-hydroxyphenyl)butan-2-one

4-hydroxybenzaldehyde

( E )-4-(4-hydroxyphenyl)but-3-en-2-one

( E )-4-(4-hydroxyphenyl)but-3-en-2-one

4-hydroxybenzaldehyde

4-hydroxybenzyl alcohol

 

Step 1

Step 2

Step 3

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Procedure:Step 1

CH2OH

HO

R: MCPBA

R: HClS: DMF

CHO

HO

4-hydroxybenzaldehyde4-hydroxybenzyl alcohol  

Synthetic transformation 1: 4-hydroxybenzaldehyde 

Experimental 1 Add 250 mg MCPBA (1 mmol) in 5 mL of freshly distilled DMF. Add dropwise to 4-hydroxybenzyl alcohol. Mix the alcohol in a solution of HCl and DMF (0.1 mL of 1M solutionof dry HCl in DMF) in 5 mL of DMF at room temperature. Stir reaction for 5 minutes and pour

into cold aqueous 5% K 2CO3. Extract with diethyl ether (2x15 mL). Wash extracts with aqueous5% K 2CO3 (2x15 mL) and dry with MgSO4. This creates 4-hydroxybenzaldehyde.

Expected yield: 100 % 122g

Safety, disposal and green issues 1:

4-hydroxybenayl alcohol: This compound is photo-sensitive. It must be kept under nitrogen. Itis also sensitive to air and an irritant to skin and eyes. Wear gloves and protective eye/facecovering.

MCPBA: This compound is an oxidizing agent. It is corrosive and may cause fire and burns.

Keep in a cool place and keep bottle tightly closed. Do not heat over 40 degrees C. Keep handsand eyes covered.

Step 2

CHO

HO

Me2CO

C: NaOH S: H2O

R: AcOH

O

CH3

HO

( E )-4-(4-hydroxyphenyl)but-3-en-2-one4-hydroxybenzaldehyde

 

Synthetic Transformation of ( E )-4-(4-hydroxyphenyl)but-3-en-2-one

Experimental 2 Pour acetone and 4-hydroxybenzaldehyde in equimolecular conditions withglacial acetic acid and heat up at the reflux condenser. Extract using NaOH. In the original procedure, the aldehyde was extracted using rhodaninic acid.

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 Expected yield: 96 % 117.12g

Safety, disposal and green issues 2:

Sodium hydroxide: This substance is corrosive and causes severe burns. Keep under argon. It is

also sensitive to carbon dioxide. Wear gloves and goggles when handling.

Acetic Acid: This compound is corrosive and also flammable. It causes severe burns. Do not

inhale.

Step 3

O

CH3

HO

CH2CH2COMe

HO

R: Zn, CH3OH, H2O

4-(4-hydroxyphenyl)butan-2-one( E )-4-(4-hydroxyphenyl)but-3-en-2-one  

Synthetic Transformation of 4-(4-hydroxyphenyl)butan-2-one (raspberry ketone) 

Experimental 3 Use a three-necked flask, fitted with a reflux condenser and septa and purgewith nitrogen gas 15 min. Make a zinc/THF slurry and transfer to the flask dropwise. Heat Znsuspension to reflux. Add methonal solution of ( E )-4-(4-hydroxyphenyl)but-3-ene-2-one and add

water in the ratio of THF:methanol:water used 7:5:1. Reflux 2.5 hours under nitrogen. Cool andflood with 150 mL of ether. Extract successively with 10% ammonium chloride (25 mL), 10%sodium bicarbonate (25 mL), and saturated sodium chloride (25 mL). Dry over anhydrousmagnesium sulfate and strip solvents by rotary evaporation. In the original procedure, it was

stated to use argon gas instead of nitrogen. Characterization of the final compound can be done

with NMR analysis using CDCl3 for analysis.

Expected yield: 100 % 117.12g

Safety, disposal and green issues 3:

Acetic Acid: This compound is corrosive and also flammable. It can cause severe burns. Do not

inhale.

Zinc: Zinc is dangerous for the environment especially the aquatic environment. It must be

disposed of in a secure container labeled hazardous waste. Release into the environment should

 be avoided.

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THF: This compound tends to form peroxides on storage in air. As a result, THF should not be

distilled to dryness, which can leave a residue of highly-explosive peroxides. Take precautionary

measures against static discharges. Do not empty into drains.

Ammonium chloride: This compound is harmful if swallowed and toxic if it comes in contact

with skin or inhaled. If it comes in contact with water, toxic gas is liberated. It can be highlyflammable. It can cause severe burns and irritates eyes. Do not breathe dust.

Overall budget: 

Chemical Supplier Cost Amount

Needed

Total

4-hydroxybenzyl alcohol Aldrich $70.50/25 g 122 mg $0.34

MCPBA Aldrich $62.80/100 g 250 mL $157

HCl Sigma $43.40/100 mL ~20 mL $8.86

DMF Sigma $33.80/500 mL 5 mL $0.3410 M NaOH in H2O Fluka $55.80/100 mL ~20 mL $11.16

AcOh Sigma $67.30/100 mL ~25 mL $16.83

Zinc Riedel-de Haeel $39.70/500 g ~130 g $10.32

K 2CO3  Sigma $42.30/500 g ~30 mL $5.08

MgSO4  Fluka $41.30/250 g ~ 5 g $0.83

Diethyl Ether Fluka $96.40/2.5 L ~30 mL $1.16

Acetone Aldrich $46/1 L ~25 mL $1.15

THF Sigma $46.50/1 L 25 mL $0.02

Ammonium chloride Sigma $30.20/500 g 25 mL $1.21

Sodium chloride Fluka $21.10/100 mL 25 mL $5.28

Total costs per synthesis: $219.58 

References:

Step 1:Yong, J.; Guo, M. Faming Zhanli Shengqing Gongkai Shuomingshu, 1995, 25, 1097729.

Kim H. R.; Jung J. H.; Kim J. N.; Ryu E. K. Synthetic Communications, 1990, 20(5), 637-640.

Step 2:Andreasch, Rudolph; Zipser, Arthur Over Substituted Rhodaninic Acid and Their AldehydeCondensation Products (machine translation)  Monatshefte fuer Chemie 1904, 25, 159-80.

Yong, J.; Guo, M. Faming Zhanli Shengqing Gongkai Shuomingshu, 1995, 25, 1097729.

Step 3:

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Kroemera J. ;Kirkpatricka C.,Mariclea B.; Gawrycha R., Moshera M.D. Tetrahedron Letters,2006, 47 (36 ), pp 6339-6341.

Yong, J.; Guo, M. Faming Zhanli Shengqing Gongkai Shuomingshu, 1995, 25, 1097729.