SUPPORTING INFORMATION
A Multi-step Synthesis Featuring Classic Carbonyl Chemistry for the
Advanced Organic Chemistry Laboratory
David B. Duff, Tyler G. Abbe, and Brian C. Goess*
Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, South
Carolina 29613
brian.goess@furman.edu
Contents:
Hazards (reproduced from the original article)
Student procedure
Annotated procedure with Instructor Notes
List of required reagents (with CAS registry numbers)
1
H NMR assignments for purified intermediates 1, 2, and 5. 1 and 2 were prepared by an
instructor via distillation of crude material. 5 is an actual spectrum obtained by students.
1
H NMR spectra of crude intermediates 1 and 2 and product 5, each as obtained by
students. Two spectra of crude product 5 are provided at the end, illustrating the range of
crude product purity commonly prepared by students in this synthesis. The latter has
been annotated for clarity.
Hazards
All reactions should be carried out in fume hoods, and students should wear
appropriate protective clothing, including goggles, gloves and coat. Sodium hydroxide,
potassium hydroxide, methylene chloride, and p-toluene sulfonic acid monohydrate are
contact and inhalation hazards. Sodium ethoxide, aqueous hydrochloric acid, and aqueous
sulfuric acid are corrosive and cause burns. Diethyl malonate is an irritant and is
flammable. Hexanes are flammable and are a neurotoxin. Acetone and ethyl acetate are
flammable. Ether is flammable and may form explosive peroxides on prolonged
exposure. Isobutyraldehyde has an unpleasant aroma. Silica gel and benzene are known
human carcinogens. No level of exposure to a known human carcinogen is considered
safe; therefore, all manipulations involving these chemicals, including the cleaning of any
glassware involved in their use and transfer, should be conducted in a fume hood under
the supervision of an instructor trained in safe chemistry laboratory practices.
1
Student Procedure
Step 1: Aldol Addition
O
O
H3C
O
H
H3C
CH3
NaOH (aq)
CH3
CH3
H3C
0 → 23 °C
OH
CH3
Combine 2.5 mL of acetone and 0.93 mL of 2.5 M sodium hydroxide (aq) in a 50 mL
round-bottom flask equipped with a stir bar. Stir for 15 min, then cool the solution to 0
°C in an ice-water bath. Meanwhile, prepare a solution of 1.24 mL of isobutyraldehyde
dissolved in 2.5 mL acetone, then add this solution dropwise to the chilled solution over a
15-min period. Then, remove the flask from the ice bath and let it warm to room
temperature while stirring for 1 h. Neutralize the reaction solution by adding 10%
hydrochloric acid (aq) dropwise via pipette until the solution reaches pH 7 according to
pH paper. Dilute the solution with 10 mL of water, transfer the liquids to a separatory
funnel, and extract the aqueous solution with diethyl ether (3 Χ 8 mL). Combine the
organic layers in the separatory funnel and wash with sat. aq. sodium chloride. Transfer
the organic layer to an Erlenmeyer flask, add approximately 3 g of anhydrous sodium
sulfate, and stir for 5 min. Filter the mixture through a Büchner funnel fitted with filter
paper, wash the solids with diethyl ether, transfer the filtrate to a tared round-bottom
flask, and concentrate the solution in a rotary evaporator. You should obtain
approximately 1.5 g of a clear oil.
Step 2: Dehydrative Elimination
O
O
CH3
H3C
OH
CH3
p-TsOH••H2O
Na2SO4
benzene
80 °C
CH3
H3C
CH3
Add 0.25 g of p-toluenesulfonic acid monohydrate and 4.0 g of anhydrous sodium sulfate
sequentially to a 25-mL round-bottom flask equipped with a stir bar. Then add 5 mL of
anhydrous benzene and your product from Step 1. Attach a reflux condenser to the
reaction flask, and lightly stopper the top of the condenser. Reflux the solution for 2.25 h.
Once complete, let the reaction flask cool to room temperature, then neutralize the
solution by adding sat. aq. sodium bicarbonate dropwise until the solution reaches pH 7
according to pH paper. Dilute the solution with 10 mL of water, transfer the solution to a
separatory funnel, and extract the aqueous layer with diethyl ether (3 Χ 10 mL). Combine
the organic layers into the separatory funnel and wash with sat. aq. sodium chloride.
Transfer the organic layer to an Erlenmeyer flask, add 3.0 g of anhydrous sodium sulfate,
and stir for 5 min. Filter the mixture through a Büchner funnel fitted with filter paper,
wash the solids with diethyl ether, transfer the filtrate to a tared round-bottom flask, and
concentrate the solution in a rotary evaporator. You should obtain approximately 1.0 g of
a light yellow oil.
2
Step 3: Dieckmann-type Annulation and Ester Hydrolysis
O
O
CH3
H3C
O
EtO
O
1) NaOEt
2) KOH (aq)
3) HCl (aq)
OEt
H3C
EtOH
78 °C
CH3
O
CH3
CO2H
To a 100-mL round-bottom flask equipped with a stir bar add 15 mL of anhydrous
(absolute) ethanol, 3.5 mL of sodium ethoxide (21 % by weight solution in ethanol), and
1.4 mL of diethyl malonate dropwise. Attach a loosely stoppered reflux condenser to the
flask, heat the solution to reflux, and stir at reflux for 15 min. While waiting, dissolve
your product from Step 2 in 5 mL of anhydrous (absolute) ethanol, and after the 15 min
of reflux add this solution to your reaction mixture dropwise through the reflux
condenser. Stir the resulting solution at reflux for 30 min. After the 30 min, remove the
stopper and add 5.1 mL of 3.8 M potassium hydroxide (aq) dropwise via pipette through
the reflux condenser, lightly stopper the condenser, and reflux the solution for 2 h. Then,
cool the solution to room temperature, remove the reflux condenser, and neutralize the
solution by adding 10% hydrochloric acid (aq) dropwise to pH 7 according to pH paper.
Step 4: Decarboxylation
O
O
H2SO4 (aq)
H3C
O
CH3
reflux
CO2H
H3C
O
CH3
Remove the ethanol from the Step 3 product solution via rotary evaporation. Note that
water will remain in the flask after the evaporation. Connect a reflux condenser to the
flask, lightly stopper the condenser, and heat the remaining solution to a gentle reflux.
Add 6 mL of a 1:5 sulfuric acid:water solution through the reflux condenser dropwise to
the stirring heated solution, and continue stirring until small bubbles of gas evolution are
no longer evident (approximately one hour). Allow the solution to cool to room
temperature, then add sat. aq. sodium bicarbonate dropwise until pH 4 according to pH
paper. Transfer the solution to a separatory funnel, and extract the aqueous solution with
methylene chloride (3 Χ 10 mL). Combine the organic layers in a separatory funnel and
wash with sat. aq. sodium chloride. Add the organic layer to an Erlenmeyer flask, add
3.0 g of anhydrous sodium sulfate, and stir for 5 min. Filter the mixture through a
Büchner funnel fitted with filter paper, wash the solids with methylene chloride, transfer
the filtrate to a tared round-bottom flask, and then concentrate the solution in a rotary
evaporator. You should obtain approximately 0.6 g of a brown oil.
3
Step 5: Column Chromatography
You may use TLC to confirm that you have the correct Step 4 product (4:1 ethyl
acetate:hexanes, product Rf = 0.3, visualized with UV irradiation). You will likely also
visualize impurities with a higher Rf that must be removed via column chromatography.
Prepare a column for chromatography using approximately 50 g of silica gel. Elute the
column with approximately 240 mL of 4:1 ethyl acetate:hexanes as the mobile phase.
Collect approximately thirty 8-mL fractions. Visualize eluted spots via UV using 4:1
ethyl acetate:hexanes as the TLC eluent. Collect all fractions containing only product
into a tared round-bottom flask, then concentrate the solution in a rotary evaporator.
4
Annotated procedure with Instructor Notes
Step 1: Aldol Addition
O
O
H3C
O
H
H3C
CH3
NaOH (aq)
CH3
CH3
H3C
0 → 23 °C
OH
CH3
Combine 2.5 mL of acetone (34.0 mmol) and 0.93 mL of 2.5 M sodium hydroxide (aq)
(2.33 mmol) in a 50 mL round-bottom flask equipped with a stir bar. Stir for 15 min,
then cool the solution to 0 °C in an ice-water bath. Meanwhile, prepare a solution of 1.24
mL (13.6 mmol) of isobutyraldehyde dissolved in 2.5 mL acetone, then add this solution
dropwise to the chilled solution over a 15-min period.
Due to isobutyraldehyde’s foul odor, we use disposable plastic syringes for this operation
and ask students to dispose of the syringe in a sharps container in a hood.
Then, remove the flask from the ice bath and let it warm to room temperature while
stirring for 1 h.
TLC cannot be used to follow this reaction due to volatility of the starting materials.
Neutralize the reaction solution by adding 10% hydrochloric acid (aq) dropwise via
pipette until the solution reaches pH 7 according to pH paper. Dilute the solution with 10
mL of water, transfer the liquids to a separatory funnel, and extract the aqueous solution
with diethyl ether (3 Χ 8 mL). Combine the organic layers in the separatory funnel and
wash with sat. aq. sodium chloride. Transfer the organic layer to an Erlenmeyer flask, add
approximately 3 g of anhydrous sodium sulfate, and stir for 5 min. Filter the mixture
through a Büchner funnel fitted with filter paper, wash the solids with diethyl ether,
transfer the filtrate to a tared round-bottom flask, and concentrate the solution in a rotary
evaporator. You should obtain approximately 1.5 g of a clear oil.
The product is somewhat volatile. Care should be taken not to heat the rotovap bath
during evaporation. We have found that trace solvent can be removed from the sample
prior to preparing an NMR sample via a brief exposure of the flask to house or high
vacuum or by blowing nitrogen over the sample for a few minutes.
Step 2: Dehydrative Elimination
O
O
CH3
H3C
OH
CH3
p-TsOH••H2O
Na2SO4
benzene
80 °C
5
CH3
H3C
CH3
Add 0.25 g of p-toluenesulfonic acid monohydrate (1.31 mmol) and 4.0 g of anhydrous
sodium sulfate (28.2 mmol) sequentially to a 25-mL round-bottom flask equipped with a
stir bar. Then add 5 mL of anhydrous benzene and your product from Step 1.
You can use up to 10 mL of benzene solvent in this reaction without increasing the
reaction time.
Attach a reflux condenser to the reaction flask, and lightly stopper the top of the
condenser. Reflux the solution using a heating mantle for 2.25 h.
We use a heating mantle (approx. 10% Variac power) for this purpose. The reaction
product is UV-active but the starting material is not. One may follow the reaction via
TLC by staining with anisaldehyde. In 1:4 ethyl acetate:hexanes, the starting material
has an Rf = 0.3 and the product has an Rf = 0.7.
Once complete, let the reaction flask cool to room temperature, then neutralize the
solution by adding sat. aq. sodium bicarbonate dropwise until the solution reaches pH 7
according to pH paper. Dilute the solution with 10 mL of water, transfer the solution to a
separatory funnel, and extract the aqueous layer with diethyl ether (3 Χ 10 mL). Combine
the organic layers into the separatory funnel and wash with sat. aq. sodium chloride.
Transfer the organic layer to an Erlenmeyer flask, add 3.0 g of anhydrous sodium sulfate,
and stir for 5 min. Filter the mixture through a Büchner funnel fitted with filter paper,
wash the solids with diethyl ether, transfer the filtrate to a tared round-bottom flask, and
concentrate the solution in a rotary evaporator. You should obtain approximately 1.0 g of
a light yellow oil.
The product is somewhat volatile. Care should be taken not to heat the rotovap bath
during evaporation beyond what is required for the removal of benzene. Given the
toxicity of benzene, we recommend performing rotary evaporation in a fume hood. We
have found that trace solvent can be removed from the sample prior to preparing an
NMR sample via a brief exposure of the flask to house or high vacuum or by blowing
nitrogen over the sample for a few minutes.
Step 3: Dieckmann-type Annulation and Ester Hydrolysis
O
O
CH3
H3C
EtO
O
1) NaOEt
2) KOH (aq)
3) HCl (aq)
O
OEt
EtOH
78 °C
CH3
H3C
O
CH3
CO2H
This reaction is somewhat water sensitive. Students should be advised to take
precautions to avoid water contamination during the procedure.
6
To a 100-mL round-bottom flask equipped with a stir bar add 15 mL of anhydrous
(absolute) ethanol, 3.5 mL of sodium ethoxide (21 % by weight solution in ethanol, 9.4
mmol), and 1.4 mL of diethyl malonate (9.3 mmol) dropwise.
Sodium ethoxide in ethanol is very hygroscopic and reacts violently with water. We
recommend that students withdraw this reagent via a new plastic syringe and that they
rinse out their syringe and needle with an inert solvent, like diethyl ether, prior to
disassembling it. The bottle may come with a SureSeal, which can be replaced with a
rubber septum if desired, but if the bottle of reagent is to be stored for some period, we
suggest replacing the volume of withdrawn solvent with an inert gas.
Attach a loosely stoppered reflux condenser to the flask, heat the solution to reflux, and
stir at reflux for 15 min.
We use a heating mantle (approx. 10% Variac power) for this purpose.
While waiting, dissolve your product from Step 2 in 5 mL of anhydrous (absolute)
ethanol, and after the 15 min of reflux add this solution to your reaction mixture dropwise
through the reflux condenser. Stir the resulting solution at reflux for 30 min.
The starting material and reaction intermediate are both UV-active. In 1:1 ethyl
acetate:hexanes, the starting material has an Rf = 0.9 and the product has an Rf = 0.2.
After the 30 min, remove the stopper and add 5.1 mL of 3.8 M potassium hydroxide (aq)
(19.4 mmol) dropwise via pipette through the reflux condenser, lightly stopper the
condenser, and reflux the solution for 2 h. Then, cool the solution to room temperature,
remove the reflux condenser, and neutralize the solution by adding 10% hydrochloric
acid (aq) dropwise to pH 7 according to pH paper.
One may store this solution for at least one week at room temperature without
detrimental effect. Alternately, if time permits, you may remove the ethanol from the
solution via rotary evaporation at this point. You will still have water left in the solution
at the end of the evaporation, which is used as solvent in the next step.
Step 4: Decarboxylation
O
O
H2SO4 (aq)
H3C
O
CH3
reflux
CO2H
H3C
O
CH3
Remove the ethanol from the Step 3 product solution via rotary evaporation. Note that
water will remain in the flask after the evaporation.
7
The rotovap bath will likely have to be heated to remove the ethanol, but at this point the
products are no longer volatile. It is not critical that all ethanol be removed.
Connect a reflux condenser to the flask, lightly stopper the condenser, and heat the
remaining solution to a gentle reflux. Add 6 mL of a 1:5 sulfuric acid:water solution
through the reflux condenser dropwise to the stirring heated solution, and continue
stirring until small bubbles of gas evolution are no longer evident (approximately one
hour). Allow the solution to cool to room temperature, then add sat. aq. sodium
bicarbonate dropwise until pH 4 according to pH paper. Transfer the solution to a
separatory funnel, and extract the aqueous solution with methylene chloride (3 Χ 10 mL).
Combine the organic layers in a separatory funnel and wash with sat. aq. sodium
chloride. Add the organic layer to an Erlenmeyer flask, add 3.0 g of anhydrous sodium
sulfate, and stir for 5 min. Filter the mixture through a Büchner funnel fitted with filter
paper, wash the solids with methylene chloride, transfer the filtrate to a tared roundbottom flask, and then concentrate the solution in a rotary evaporator. You should obtain
approximately 0.6 g of a brown oil.
Students may use TLC to confirm that they have the correct Step 4 product (4:1 ethyl
acetate:hexanes, product Rf = 0.3, visualized with UV irradiation). They will likely also
visualize impurities with a higher Rf that must be removed via column chromatography.
Step 5: Column Chromatography
You may use TLC to confirm that you have the correct Step 4 product (4:1 ethyl
acetate:hexanes, product Rf = 0.3, visualized with UV irradiation). You will likely also
visualize impurities with a higher Rf that must be removed via column chromatography.
Prepare a column for chromatography containing approximately 50 g of silica gel.
We wet load our columns, mixing the appropriate amount of silica gel with eluent before
pouring the mixture into the column. The column we used is 1” in diameter. The
separation is not particularly difficult, so this procedure is likely quite adaptable to any
particular column parameters. The chromatography can be conducted much more
quickly if air pressure is used to flush eluent through the column (flash chromatography).
We recommend this option if the appropriate glassware is available, but students should
then be cautioned about the hazards associated with the use of pressurized glassware.
Elute the column with approximately 240 mL of 4:1 ethyl acetate:hexanes as the mobile
phase. Collect approximately thirty 8-mL fractions. Visualize eluted spots via UV using
4:1 ethyl acetate:hexanes as the TLC eluent. Collect all fractions containing only product
into a tared round-bottom flask, then concentrate the solution in a rotary evaporator.
The impurities usually begin to elute around fraction 7. The product usually elutes
between fractions 14 and 24. We sometimes observe mixing of product with impurities in
the early product-containing fractions (closer to fraction 14).
8
List of required reagents (with CAS registry numbers)
The following reagents were purchased from Aldrich, ACS reagent grade unless
otherwise noted. Liquids and solids were purchased anhydrous unless otherwise noted.
Acetone [67-64-1]
Isobutyraldehyde, 99% [78-84-2]
Sodium hydroxide [1310-73-2]
p-Toluenesulfonic acid monohydrate [6192-52-5]
Sodium sulfate, granular [7757-82-6]
Benzene [71-43-2]
Diethyl malonate, 99% [105-53-5]
Absolute ethanol [64-17-5]
Sodium ethoxide (21 wt. % in ethanol) [141-52-6]
Potassium hydroxide [1310-58-3]
Sulfuric acid, concentrated [7664-93-9]
The following reagents, used in work-up and chromatography, were purchased from
Fisher:
Hydrochloric acid, 37% [7647-01-0]
Magnesium sulfate, anhydrous [7487-88-9]
Diethyl ether [60-29-7]
Ethyl acetate [141-78-6]
Hexanes [92112-69-1]
Dichloromethane [75-09-2]
Sodium bicarbonate [144-54-8]
Sodium chloride [7647-14-5]
1
H NMR data (CDCl3) for purified intermediates (1 and 2) and product (5)
Hg
Hf
Hb3C
Hc
CHa3
1
O
O
Hn
CHh3
He
OHd
Hj3C
Ht
CHp3
Hk
Hm
CHj3
O
O
Hu
Hq3C
Hr
2
Hv
Hs
CHq3 Ht
5k
Hu
O
Hw
H3C
OH
CH3
5e
Intermediate 1, purified by distillation: 3.76-3.82 (m, He), 2.96 (bs, Hd), 2.44-2.60 (m, Hf,
Hg), 2.14 (s, Hh), 1.58-1.66 (m, Hc), 0.84-0.92 (m, Ha, Hb)
Intermediate 2, purified by distillation: 6.72 (dd, Hm), 5.99 (d, Hn), 2.40-2.46 (m, Hk),
2.12 (s, Hp), 1.03 (d, Hj)
Final product 5, purified by column chromatography: 5.42 (s, Hw), 3.38 (d, Hv), 2.68 and
2.40 (dd, Ht and dd, Hu), 1.82-1.90 and 1.58-1.68 (m, Hr and m, Hs), 0.96 (d, Hq)
9
1
H NMR spectra
10
11
12
13
14
15
16