Multistep synthesis of 5‐isopropylcyclohexane‐1,3‐dione Purpose: To synthesize 5‐isopropylcyclohexane‐1,3‐dione in good yield and high purity from inexpensive starting materials. Main reactions: Step 1: Aldol Addition
O
O
H3C
O
H
CH3
H3C
NaOH (aq)
CH3
0 23 °C
CH3
H3C
OH
CH3
Combine 2.5 mL of acetone and 0.93 mL of 2.5 M sodium hydroxide (aq) in a 50 mL roundbottom flask equipped with a stir bar. Stir for 15 min, then cool the solution to 0 °C in an icewater 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
 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. Obtain IR and proton NMR of unpurified product.
Discussion: Do your data confirm that you produced your intended product? Explain. How
pure is your compound? If there are impurities, do you know their identities? What was your %
yield? Overall, how effective was this reaction? What would you do to improve it in the future?
Step 2: Dehydrative Elimination
O
O
p-TsOHH2O
Na2SO4
CH3
H3C
OH
benzene
80 °C
CH3
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 x 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. Obtain IR and proton NMR of unpurified product.
Discussion: Do your data confirm that you produced your intended product? Explain. How
pure is your compound? If there are impurities, do you know their identities? What was your %
yield? Overall, how effective was this reaction? What would you do to improve it in the future?
Step 3: Dieckmann-type Annulation and Ester Hydrolysis
O
O
CH3
H3C
EtO
CH3
O
1) NaOEt
2) KOH (aq)
3) HCl (aq)
O
OEt
EtOH
78 °C
H3C
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. (No characterization at this step.)
Discussion: Do your data confirm that you produced your intended product? Explain. How
pure is your compound? If there are impurities, do you know their identities? What was your %
yield? Overall, how effective was this reaction? What would you do to improve it in the future?
Step 4: Decarboxylation
O
O
H2SO4 (aq)
H3C
O
CH3
CO2H
reflux
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  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. Obtain proton NMR of
unpurified product.
Discussion: Do your data confirm that you produced your intended product? Explain. How
pure is your compound? If there are impurities, do you know their identities? What was your %
yield? Overall, how effective was this reaction? What would you do to improve it in the future?
Step 5: Column Chromatography
Work with a partner for this step. Between the two of you, purify approximately 0.6 g of impure
oil. To save time, one partner can be obtaining data for the purified product while the other is
finishing the column,
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. Obtain TLC data, IR,
proton and 13C NMR data for the final product as time allows.
Discussion: What was your overall % yield for the multistep reaction? Which step would you
work on first to improve the overall synthesis? Consult aldrish.com to find the prices of the
starting materials and the product. Based on these costs, was this an efficient synthesis?
Lab 7 assignment: Turn in a hardcopy of a full formal lab report, with your lab notebook
(carbon copy or photocopy) and spectra attached. Turn in an electronic copy of the formal
report.
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Due at the beginning of lab the week of December 1
100 pts based on in-lab performance, written communication, and correctness of content
Electronic submission of introduction to turnitin.com
For the introduction section, refer to two of the following papers. You must access them
through the IU Chemistry Library page or in the chemistry library. While you do not
have to understand everything in them, you should not read one sentence and cite the
source—it is easy to tell if you have read enough to understand the main point of the
paper before citing it. Use these references to discuss previous work, summarize the
understanding of the field, or point out why the current study is important. The
introduction should be 2-3 paragraphs.
o An article discussing enzymatic biosynthesis using aldol reactions in a multistep
synthesis: Advanced Synthesis and Catalysis (2014) 356 (14-15) pp 3007-3024.
o An aldol reaction utilized to form derivatives of a useful drug from cheap,
commodity chemicals: Chemical and Pharmaceutical Bulletin (2012) 60(4) pp
557-561.
o Stereochemistry can be controlled through multistep aldo-type reactions: Journal
of Organic Chemistry (2010) 75(12), 4201-4211.
o Review of useful c-c bond formation, including Dieckmann-type reactions, in
biologically active compounds: Advanced Synthesis and Catalysis (2001) 343(2)
143-159.
o Other of your choice—discuss with instructor or AI.