Dimedone week 1

Experiment 4
Synthesis of Dimedone
Dimedone will be synthesized so as to be
used in the next experiment.
O O
CH 3O OCH 3
Dimethyl malonate
O O
CH3O OCH3
O O 1)
CH 3O OCH 3
NaOCH3, HOCH3
O O
CH 3O OCH 3
O O
CH 3O OCH 3
O O
CH3O OCH3
pKa ~ 10-12 for active methylene compounds
O
2) NaOH, water,heat
3) HCl, water, heat
(mesityl oxide)
O O
dimedone
1

Let’s look at the experiments we have
done so far:
Exp 1 (Cycloaddition) , Exp 2 (Nitration of
Naphthalene) and Exp 3
(Aldol/dehydration): Mix substances,
isolate product, recrystallize
Exp 4 (Synthesis of Dimedone):
Mix substances, then hydrolyze, then
decarboxylate. Eventually isolate product
and recrystallize.
More steps – more chances for lower
product yield AND purity.
Lower yield:
�Glassware must be dry
�If too much solvent is used in
recrystallization step, lower yield
Lower purity:
�If recrystallized product not
properly washed, lower purity
2

Step 1:
O O
CH 3O OCH 3
O
H
O
H
H
H
H
H H
O
O OCH 3
OCH 3
Keto-enol tautomerism
(see Vollhardt, p. 772)
O
H
O OCH3 H
OCH 3
Na OCH3
O O
HOCH 3 CH 3O OCH 3
The anion of dimethyl
malonate adds in a 1,4addition.
CH 3 O H
OCH3
CH3O H
O
O
H
O
1
3
2
4
O
O OCH 3
O
O OCH 3
OCH 3
OCH 3
There are three sets of acidic protons.
Let’s pull off one of the H , follow it
through, and then explain why the other
types of protons don’t lead to a product.
3

pKa ~ 19 H
H
O
H
H
O
H
O OCH3 H
pKa ~ 19
O
O O
OCH 3
pKa ~10
OCH3
+ OCH 3
Na OCH3
O
O
3
2
1
3 4
2
4
5
CH 3O
1
6
5
O
O
6
O
OCH 3
OCH 3
O
OCH 3
If you take off a H or a H proton and try to do the
cyclization, you will produce a 4-membered ring
(see Vollhardt, Chapter 23) – not allowed.
O
H
H
H
H
O
H
O
H
OCH 3
OCH 3
N a O CH 3
O
H
1
H
H
O
1
O
2
3
H
4
O OCH3 H
X
2 3
O
4
O
OCH 3
OCH3
OCH 3
not allowed
4

Step 2:
O
O O
O O
OH
O OH
OCH 3
OCH 3
NaOH(aq)
K = 1
O O
OCH3
K=10 11
O
O O
CO 2
O H
+ CH 3 OH
"drives"
hydrolysis
pKa ~ 5
Esters react with – OH, therefore must
keep H 2O out of reaction of dimethyl
malonate with mesityl oxide
*** CH 3OH removed BEFORE acid
hydrolysis (step 3) by rotary evaporator;
equilibrium will favor carboxylate.
Hydrolysis reaction temperature, for step
3, will be higher without methanol
present.
***
5

Step 3:
O O
CO 2
H
O O H
H
O O H
H3O + (aq)
pKa ~ -2
K = 10 7
H O H
H
acid catalyzed Enol-
Keto Equilibration
(see Vollhardt, p 772)
H O H
ΔG ~ -17 Kcal/mol; K = 10 17
4
O
5
O O
6
3
O 2
O O H
an enol
O O
H H
pKa ~ 5.25, therefore
the final solution must
be acidic
H 1
+ CO 2
+ H 3 O +
6

Equipment for top equipment drawer:
1. 250 mL one neck, round bottomed 24/40 flask
2. reflux condenser with 24/40 standard taper joints
3. 3 – 10 mL graduated cylinders
4. 1 – 25 mL graduated cylinder
5. 2 – 50 mL graduated cylinders
6. 125 mL Erlenmeyer flask (to recrystallize crude dimedone)
7. 250 mL filter flask
8. small Büchner funnel
9. Large black filter adapter (#3) for 250mL filter flask.
10.2 – 200 mm double blade, stainless steel spatulas
11.cork ring
12.plastic stoppers for 24/40 standard taper joint
13.drying tube
14.one watch glass
15.one stirring rod
PROCEDURE:

Useful data: Sodium methoxide, FW 54.02
25 wt% NaOCH3 in methanol; d 0.945 g/mL
Dimethyl malonate, FW 132.12; d 1.156 g/mL
Mesityl oxide, FW 98.15; d 0.858 g/mL
Minimize exposure of methanol or the reaction in progress to the atmosphere since
these absorb moisture. You must get to the point of adding the 6 M HCl to the reaction
before you leave lab the first day. If not, you will have to repeat the experiment.
Place 12 mL of 25 wt% sodium methoxide solution in methanol in a 250 mL round
bottomed flask equipped with a 24/40 standard taper joint. Add 5.7 mL of dimethyl
malonate to the flask followed by a boiling stone. A small amount of solid may form
when the dimethyl malonate is added (What is it likely to be?). Lightly grease the male
24/40 standard taper joint of a reflux condenser and attach the condenser to the flask.
(Note: It is important to lightly grease a standard taper joint that will be heated in the
presence of base or stored for an extended period. Otherwise, the joint is likely to seize.)
Attach a drying tube containing calcium chloride (aka Drierite) to the reflux condenser.
Heat the reaction mixture to reflux using a sand bath. After 5 min at reflux, remove the
reaction flask from the sand bath and let it cool for about 5 min. Briefly remove the drying
tube from the reflux condenser and, with stirring, add 6.0 mL of mesityl oxide in several

portions into the flask through the condenser over ca. 2 min. Then reattach the drying tube
and reheat the reaction mixture to reflux for 30 minutes. Cool the reaction flask to room
temperature and remove the reflux condenser. Attach the reaction flask to a rotary
evaporator and remove the methanol by rotary evaporation, while heating the flask with a
warm water bath. When the standing liquid has been evaporated, remove the flask from
the rotary evaporator. (The solid remaining in the flask will still be moist at this point.)
Add 40 ml of 3 M aqueous NaOH solution to the reaction flask, attach the reflux
condenser, and reheat the reaction mixture to reflux for 40 min using the sand bath.
Remove the flask from the sand bath.
Add 35 mL of a 6 M aqueous HCl solution to a 250 mL Erlenmeyer flask containing
a boiling chip. While manually swirling the Erlenmeyer flask, carefully pour the warm
reaction mixture into the flask. Check to see that the pH of the solution is about 1. If not,
add more HCl solution in small portions and recheck the pH. Place a small watch glass
over the mouth of the Erlenmeyer flask and boil the mixture gently, with stirring, for ca.
10 min., until no more gas is evolving. At this stage the reaction can be left until the next
lab period. If you choose to do this, loosely stopper the flask with a cork and carefully
place the flask in YOUR STUDENT drawer. You must get a 250mL Erlenmeyer flask
from the TA to put in your equipment drawer TO REPLACE the flask you were using this

session; otherwise you will be penalized. If you have time, however, collect the crude
dimedone product as described below.
MAKE SURE YOU HAVE A REAGENT TABLE WITH YOUR PLAN WHEN YOU
COME TO LAB.