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 known
as raspberry ketone. Raspberry ketone is the primary aroma of red raspberries. It is often
industrially produced for perfumery, cosmetics, and food additives. Studies have also shown that
when given to mice in large doses, it can assist in preventing obesity.
Overall Reaction Scheme:
Step 1

CHO

CH2 OH

R: MCPBA
R: HCl
S: DMF

HO

HO

4-hydroxybenzaldehyde

4-hydroxybenzyl alcohol

Step 2

CHO

C: NaOH S: H2O
Me2CO

CH3

R: AcOH

HO

4-hydroxybenzaldehyde

HO

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

Step 3
CH3

CH2 CH 2 COMe

R: Zn, CH3COOH

HO
HO

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

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

Procedure:
Step 1
CHO

CH2 OH

R: MCPBA
R: HCl
S: DMF

HO

HO

4-hydroxybenzaldehyde

4-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 4hydroxybenzyl alcohol. Mix the alcohol in a solution of HCl and DMF (0.1 mL of 1M solution
of dry HCl in DMF) in 5 mL of DMF at room temperature. Stir reaction for 5 minutes and pour
into cold aqueous 5% K2CO3. Extract with diethyl ether (2x15 mL). Wash extracts with aqueous
5% K2CO3 (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. It
is also sensitive to air and an irritant to skin and eyes. Wear gloves and protective eye/face
covering.
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 hands
and eyes covered.

Step 2
O
CHO

C: NaOH S: H2O
Me2CO

CH3

R: AcOH

HO

4-hydroxybenzaldehyde

HO

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

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

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

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

CH2 CH 2 COMe

R: Zn, CH3OH, H2O

HO
HO

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

4-(4-hydroxyphenyl)butan-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 purge
with nitrogen gas 15 min. Make a zinc/THF slurry and transfer to the flask dropwise. Heat Zn
suspension 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 and
flood 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 anhydrous
magnesium 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.

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 highly
flammable. It can cause severe burns and irritates eyes. Do not breathe dust.

Overall budget:
Chemical

Supplier

Cost

4-hydroxybenzyl alcohol
MCPBA
HCl
DMF
10 M NaOH in H2O
AcOh
Zinc
K2CO3
MgSO4
Diethyl Ether
Acetone
THF
Ammonium chloride
Sodium chloride

Aldrich
Aldrich
Sigma
Sigma
Fluka
Sigma
Riedel-de Haeel
Sigma
Fluka
Fluka
Aldrich
Sigma
Sigma
Fluka

$70.50/25 g
$62.80/100 g
$43.40/100 mL
$33.80/500 mL
$55.80/100 mL
$67.30/100 mL
$39.70/500 g
$42.30/500 g
$41.30/250 g
$96.40/2.5 L
$46/1 L
$46.50/1 L
$30.20/500 g
$21.10/100 mL

Amount
Needed
122 mg
250 mL
~20 mL
5 mL
~20 mL
~25 mL
~130 g
~30 mL
~5g
~30 mL
~25 mL
25 mL
25 mL
25 mL

Total
$0.34
$157
$8.86
$0.34
$11.16
$16.83
$10.32
$5.08
$0.83
$1.16
$1.15
$0.02
$1.21
$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 Aldehyde
Condensation Products (machine translation) Monatshefte fuer Chemie 1904, 25, 159-80.
Yong, J.; Guo, M. Faming Zhanli Shengqing Gongkai Shuomingshu, 1995, 25, 1097729.
Step 3:

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.