PHAR 2034: Synthesis of Complex Drugs
Synthesis Grignard reagent, phenyl magnesium bromide and its
reaction with Ethyl acetoacetate ethylene ketal
Abstract
Phenylmagnesium bromide is a Grignard reagent which is used to reduce the ester group in
Ethyl acetoacetate ethylene ketal, which was produced in the first practical. It is a molecule
whereby one carbonyl group was protected in order to synthesize 2-(2-methyl-1,3-dioxolan-2-
yl)-1,1-diphenylethan-1-ol which was then purified by recrystallization from petroleum ether.
The product resulted in 0.5772g of spiked and translucent pale crystals.
Aim
The aim of this practical is to synthesis phenyl magnesium bromide which acts as the Grignard
reagent and then react it with Ethyl acetoacetate ethylene ketal to form product, 2-(2-methyl-
1,3-dioxolan-2-yl)-1,1-diphenylethan-1-ol. One of the carbonyls in the products was protected
in practical hence the protection needs to be removed, that will be done in the third practical
Methods
Synthesis of a Grignard reagent
This reaction needs to be done in the fume cupboard using a reflux apparatus.
1.34g of magnesium turnings were weighed and added to a 100mL two necked flask along
with a single crystal of iodine and a magnetic stirrer. The 100mL two necked flask was then
assembled with a dropping funnel and condenser, with the 100mL two necked flask on top of a
hotplate to form the reflux apparatus.
10mL of dry diethyl ether is then added to the magnesium turnings using the dropping funnel
while rapidly stirring on a hotplate.
7.85g of bromobenzene was then weight out in a vial along with 5mL of dry diethyl ether which
was then added to the closed dropping funnel. An additional 5mL of dry diethyl ether is added
to the vial to rinse out the residual bromobenzene which is added to the dropping funnel and
then sealed with a rubber bung.
The condenser flow was switched on and then about 2mL of the solution is released while
stirring on the hotplate. After an observant color change from orange to colorless to dark
grey/green and visible refluxing, the bromobenzene solution was slowly added over a period of
10 minutes. After the addition, the solution is left for an additional 10 minutes under reflux.
After that, the reaction mixture will need to be cooled to 0°C in an ice bath
Reaction of the Grignard reagent
While the solution is refluxing, a separate solution is prepared with the ester from the first
experiment (4.35g) in 10mL of dry diethyl ether which is then added to the dropping funnel
while its sealed.
Once the reaction mixture has reached the desired temperature of 0°C, add the ester solution
very slowly over a period of 10 minutes while vigorously stirring using the hotplate under the
ice bath. The addition of the ester solution is done while the reaction mixture is on an ice bath.
After the addition of the ester solution, the water bath was removed, and the reaction mixture
was left to be stirred for another hour
40g of ice is added to the 250mL beaker to where the reaction mixture is carefully added,
this is done to quench any remaining Grignard reagent (you may need to use a spatula to
help break up the solids), then 10 mL of diethyl ether is added (and mixture is stirred until
the gummy yellow solids (product) is dissolved and the mixture stirs freely). The yellow
ether layer is carefully decentered into an Erlenmeyer flask. The mixture is then washed
twice with 10 mL of water. Glacial acetic acid is then added to the mixture dropwise while
being vigorously stirred until it goes clear
The reaction mixture is then transferred to a 100mL separatory funnel where is it
separated to remove the bottom (aqueous) layer in a conical flask and the ether layer is
removed in another conical flask that is preserved for later. The aqueous layer is returned
in the separatory funnel where it’s washed with 20mL of diethyl ether to extract the ether
layer. Both the extracted ether layers are combined and then washed twice with 20mL of
sodium hydrogen carbonate, 20mL of water and then 20mL of brine. The aqueous layer from
each washed is discarded. Magnesium sulfate is added to the ether layer to dry it and then it is
filtered using a filter paper into a 100mL round bottom flask. The filtered ether solvent is then
placed in a rotary evaporator to give a small amount of yellowish liquid (crude tertiary alcohol)
with some solid particulates visible.
Recrystallisation of the product
Slowly add just enough ether to dissolve the product using a glass pipette and then petroleum
ether is slowly added to the solution until a white precipitate forms and no more precipitate
forms. After few crystals start to form, the solution is filtered using a Buchner filter to extract all
the white crystals formed
Results and discussions
Figure 1; This shows the NMR spectrum of the product formed
Peak Chemical Integral Multiplicity J Assignment Interpretation
shift (ppm) (Hz)
1 0.86- 1.54 3H CH3 These show the presence
of the saturated alkyl
groups
2 2.83 2H CH2 These show the presence
of the saturated alkyl
groups
3 3.64 2H CH2 These show the presence
of the saturated alkyl
groups
4 3.87 2H CH2 These show the presence
of the saturated alkyl
groups
5 3.855 2H CHO This indicated the presence
of the two ester groups
6 5.37 1H OH This indicates the presence
of an alcohol group
7 7.18-7.52 10H Aromatic These peaks show the
presence of the two
benzene rings in the
molecule
Table 1; This illustrates the interpretation of the peaks formed by the product on the NMR
spectrum
Figure 2a; This is the structure of the product formed
Figure 2b; This is the structure of the product formed with the NMR peaks indicated on
them
Weight Molecular
Compound Moles
(g) mass
2-(2-methyl-1,3-dioxolan-2-
0.5772 284.3 0.00203
yl)-1,1-diphenylethan-1-ol
Ethyl acetoacetate ethylene
2.8763 174.1944 0.016512
ketal
Magnesium 1.3709 24.305 0.056404
Bromobenzene 7.85 157.01 0.0499968
Table 2; it illustrates the amount of each product used and their calculated moles which can be
used to find the percentage yield
As seen in table 2, Ethyl acetoacetate ethylene ketal is seen to be the limiting reagent hence
can be used to calculate the percentage yield as shown below.
The percentage yield of 2-(2-methyl-1,3-dioxolan-2-yl)-1,1-diphenylethan-1-ol was calculated
to be 12.3%. Low yield may be as a result of impurities in the Grignard reagent, the reagent
may have not fully converted to the desired product or unsuitable reaction conditions like
temperate or solvent
The melting point range of 2-(2-methyl-1,3-dioxolan-2-yl)-1,1-diphenylethan-1-ol is 60-70°C as
the product starts melting at 60°C and stops melting at 70°C. This range of melting point tells
us that the product may contains impurities. However, the range is not very wide hence the
impurities present must be at a minimum which is acceptable. These impurities may have been
due to not evaporating it enough in the rotatory evaporator
Conclusions
The experiment was aimed at synthesizing of 2-(2-methyl-1,3-dioxolan-2-yl)-1,1-
diphenylethan-1-ol which was successful, however the percentage yield (12.3%) obtained was
less than expected. However, the required product was successfully synthesized (2-(2-methyl-
1,3-dioxolan-2-yl)-1,1-diphenylethan-1-ol) using the Grignard reagent (phenyl magnesium
bromide) and Ethyl acetoacetate ethylene ketal
1. Draw a complete mechanism for the ketone protection reaction in Practical 1. Explain why
the acid is catalytic.
para-toluenesulfonic acid (tosylic acid) is used as a strong acid catalyst
2. The starting material for practical one (ethyl acetoacetate) contains two carbonyl groups.
Explain why only one reacts with the protecting group.
3. Draw a complete mechanism for the Grignard reaction performed in Practical 2 (excluding
the actual formation of the Grignard).
4. Explain what precautions must be taken in a typical Grignard synthesis with regards to the
exclusion of water. Why must these precautions be taken?
These precautions must be taken as the carbon atom of the Grignard reagent can act as
strong base as well as a strong nucleophile. Hence water would deprotonate the Grignard
reagent therefor destroying it, forming a hydrocarbon
5. Why is it important to not add too much acetic acid during the work-up in practical 2?
If too much was added, you would not be able to see the transition from milky to cloudy
6. A different way of synthesizing the final product in Practical 3 (4,4-diphenylbut-3-en-2-one)
is via an aldol condensation. What starting materials would you use and what reaction
conditions would you employ? Draw the full reaction.
