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Synthesis of Hexaphenylbenzene
Synthesis Type: Multiple-step; Convergent
Synthetic Transformations Involved: Additions to alkenes; E2 elimination; aldehyde
coupling; alcohol oxidation; aldol condensation; Diels-Alder reaction
1) Synthesis
Linear synthesis I: Tetraphenylcyclopentadieneone
CHO
OH
Ph
Thiamine HCl
Ph
NaOH (aq)
Ph
Cu(OAc)2
NH4NO3
HOAc
Ph
O
O
IV-01
IV-02
O
Ph
Ph
NMe3+OH-
Ph
Ph
O
Ph
Tetraphenylcyclopentadieneone
Ph
Ph
IV-03
nBu4N+Br3-
Ph
Ph
Br
IV-04
KOH
Ph
Ph
Diphenylacetylene
IV-05
Synthesis convergence:
O
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
IV-03
Ph
IV-05
CO (g)
IV-06
The first linear synthesis shown in the scheme above begins with the conversion of
benzaldehyde to benzoin (IV-01) which is known as the benzoin condensation. The
traditional reaction conditions for such a condensation utilize cyanide as nucleophile.
However, due to the hazards involved with the handling of cyanide, a less toxic reagent,
thiamine hydrochloride, is utilized. The second step is a simple and very mild redox
reaction of IV-01 to benzil (IV-02) in which copper (II) is reduced to copper (I) and
nitrogen gas is evolved. The reaction between IV-02 and diphenylacetone in the presence
of a base is a double aldol condensation with elimination of two equivalents of water to
give enone IV-03.
The second linear synthesis shown above involves the preparation of diphenylacetylene
(IV-05). Addition of bromine to trans-stilbene yields the meso dibromide, IV-04. Rather
than using elemental bromine for this step, which is a liquid and difficult to handle, we
employ tetra-n-butlyammonium tribromide which is a solid and easier to handle. Double
elimination of IV-04 yields the desired product.
The final convergent step is a Diels Alder reaction between diphenylacetylene (IV-05)
and tetraphenylcyclopentadienone (IV-03) followed by loss of CO to give
hexaphenylbenzene (IV-06).
2) Synthetic Procedures
NOTE: For each linear synthesis, the synthetic procedures should be scaled as
required to accommodate the amount of material you have (except for the first step in a
linear sequence). You can scale up or down as required. Be sure to always retain a
sample of your intermediates for TLC comparisons, etc.
2.1 Synthesis of Benzoin (IV-01)
Vitamin B1, also known as thiamine pyrophosphate, is a coenzyme universally present in
all living systems. It was discovered as a required nutritional factor in humans by its link
to beriberi, a disease of the peripheral nervous system caused by a lack of vitamin B1, in
the diet. This substance catalyses several important biochemical reactions, including the
conversion of aldehydes to -hydroxyketones (acyloins). The related compound thiamine
hydrochloride can effect the same transformation in the absence of other biological
substances. We will take the advantage of this reactivity to produce benzoin from
benzaldehyde. You must understand the mechanism of this transformation. It can be
found in various biochemistry textbooks, as well as in "Introduction to Organic
Laboratory Techniques" by Pavia, Lampman, Kriz and Engel, from where this
experiment was adapted.
NH2
NH2
N
+
N
N
H
O P O P O
OH
Thiamine Pyrophosphate
Cl
+
N
N
H
HCl
OH
Thiamine Hydrochloride
OH
Procedure:
CHO
OH
Thiamine HCl
NaOH (aq)
Ph
Ph
O
IV-01
Add thiamine hydrochloride (750 mg) to a suitable round bottom flask. Dissolve the solid
in water (2.5 mL) by swirling, add 95% ethanol (2.5 mL) and cool the solution for a few
minutes in an ice bath. Place a stir bar in the flask and, with stirring, add 2.5 mL of 2M
NaOH. Weigh a dry vessel and add benzaldehyde (4.5 mL). Reweigh the vessel to
determine the exact mass of the benzaldehyde contained within. Dissolve the
benzaldehyde in 3 mL of 95% ethanol. (Alternatively you may use the density of
benzaldehyde to calculate the amount you use. Just be sure to utilize an accurate
measuring device (not a graduated cylinder!) and dilute in 3 mL of 95% ethanol before
the next step.) Add the resulting solution of benzaldehyde to the reaction flask. Rinse the
vessel that contained the benzaldehyde with two-1 mL portions of 3 mL of 95% ethanol
and add the rinses to the reaction flask. At this point, you can proceed in two ways to
complete the reaction. The first is the easier and tends to work better but requires more
time. The second will work if you are short on time.
Method 1: Seal the flask containing the reagents and place the round bottomed flask in a
beaker and allow to stand for a couple of days. In most cases, the product will appear as
crystals. This can stand for many days without a problem as long as the solvent does not
evaporate. Collect the product by vacuum filtration and wash the crystals with two 5 mL
portions of ice cooled water. Dry the product in a desiccator. Weigh the dry crude
product, determine the melting point and calculate the yield.
Method 2: Attach an air condenser to the round bottom flask and heat the reaction
mixture with stirring in a water bath at 60oC for about 90 minutes. At the end of the
reaction time, remove the stir bar and allow the mixture to cool to ambient temperature.
Induce crystallization of the benzoin by cooling the mixture in an ice bath. If the product
separates as an oil, reheat the mixture and allow to cool more slowly than previously. It
may be helpful to scratch the inside of the flask with a glass rod. Collect the product by
vacuum filtration and wash the crystals with two 5 mL portions of ice cooled water. Dry
the product in a desiccator.
For either method, if a solid is not obtained, DO NOT automatically start the reaction
again! Perform an extractive work up and analyze the crude product by TLC. If the
desired product appears to be present, you will need to continue your efforts to crystallize
the material. You may have success inducting crystallization by introducing a seed
crystal.
The benzoin obtained should be of sufficient purity to continue the next step. However, if
the melting point is more than 5C off the literature value, the product must be purified
by recrystallization. To select an appropriate solvent, you can start your solvent screening
by using the observations from the reaction to guide your selection. Obtain and record the
following information in your notebook. BE SURE TO NOTE WHETHER THE DATA
YOU RECORD IS OF CRUDE OR RECRYSTALLIZED MATERIAL!
1.
2.
3.
4.
5.
OH
Ph
Ph
Cu(OAc)2
NH 4NO 3
HOAc
O
IV-01
Ph
Ph
O
IV-02
add water (5 mL). Cool the reaction flask in an ice/water bath for around 10 minutes and
collect the yellow crystals of benzil (IV-02) using a Hirsch funnel. You may need to
work to induce crystallization. DO NOT DISCARD the reaction if crystals do not form!
Wash the crystals with two portions of cooled water (10 mL). The benzil obtained often
contains small amounts of unreacted benzoin which needs to be removed. Take a TLC of
the crude crystals. Recrystallize the crude material and perform another TLC analysis.
The crude benzil can also be purified using column chromatography. It is very important
that the benzil (IV-02) obtained in this step is free from benzoin (IV-01) before
conducting the next step in the synthetic sequence. To test if your product is free of
benzoin, take ca. 0.5 mg of your product, add 0.5 mL of 95% ethanol or methanol and
add one drop of 10% NaOH. If benzoin is present, a purple color will form. This color
comes from a complex that forms between benzil and the auto oxidation product of
benzoin). If you obtain a positive result, you will need to re-crystallize your material
again until the test is negative. If you do not observe a purple color, add 0.5 mg of
benzoin to see what a positive result would look like.
Obtain and record the following information in your notebook:
1.
2.
3.
4.
5.
Ph
Ph
Ph
O
Ph
Ph
Ph
O
Ph
IV-02
NMe3+OH-
Ph
Ph
IV-03
containing a stir bar. Attach an air condenser and heat the reaction at 135-145 C for 10
minutes, in which the added benzil should dissolve. Once a homogenous solution is
obtained, the heat is removed and the reaction allowed to cool to 80-100oC. While the
reaction mixture is still hot, 300 L of a 40% benzyltrimethylammonium hydroxide
solution in methanol is cautiously added with stirring. Allow the reaction mixture to cool
to room temperature. While the reaction mixture is cooled, dark purple crystals of
tetraphenylcyclopentadienone (IV-03) should be formed. Cooling the reaction flask with
water could also facilitate the formation of the crystals. Add cold methanol (4.5 mL) and
cool the mixture for 10 minutes on an ice/water bath. Collect the purple crystals by
vacuum filtration and wash the crystals with a couple mL of cold methanol in order to
remove the brown impurities. Let the crystals dry in a desiccator. Obtain and record the
following information in your notebook:
1.
2.
3.
4.
5.
6.
Br
Ph
nBu4N+Br3-
Ph
Ph
Ph
Br
IV-04
Method 1: Seal the flask containing the reagents tightly (to prevent escape of volatile and
hazardous methylene chloride! NOTE: Parafilm is NOT an effective method of capping
vessels containing organic volatiles as the parafilm material is permeable to organic
vapors. Parafilm only presents a barrier to water!) and allow to stand for a couple of days
(in a hood!). In most cases, the product will appear as crystals. This can stand for many
days without a problem as long as the solvent does not evaporate. Filter the crystalline
product from the reaction mixture by vacuum filtration. Wash the product with three
portions of cold water (10 mL each) and then with two portions of cold acetone (10 mL
each).
Method 2: Stir the reaction contents for an additional 45 minutes. During this time, the
orange colored solution gradually changes to yellow and solid should begin to form. If
time permits, a longer reaction time will result in better yields. Filter the crystalline
product from the reaction mixture by vacuum filtration. Wash the product with three
portions of cold water (10 mL each) and then with two portions of cold acetone (10 mL
each). Air dry the product on a filter paper. The product should be of sufficient purity to
be used in the next step. Obtain and record the following information in your notebook:
1.
2.
3.
4.
5.
Br
Ph
Ph
KOH
Br
IV-04
Ph
Ph
Diphenylacetylene
IV-05
temperature (it is difficult to control the temperature of a hot plate). DO NOT ALLOW
THE INTERNAL TEMPERATURE TO RISE ABOVE 195oC. You may observe
spattering if your product is wet. DO NOT LEAVE THIS REACTION UNATTENDED!
Cool the resulting dark-colored reaction mixture to 45oC in water bath. Add water (10
mL), swirl or stir until thoroughly mixed, and place the flask in an ice/water bath for 15
minutes. Collect the crystals obtained with vacuum filtration using a Hirsch funnel.
Recrystallize this material to provide a white solid (white needles). Obtain and record the
following information in your notebook:
1.
2.
3.
4.
5.
6.
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
IV-03
Ph
IV-05
CO (g)
IV-06
(IV-06) by vacuum filtration. Wash the crystals with cold hexane (2 mL) and next with
cold toluene (2 x 2 mL) to yield white crystalline product. Let the product air dry on a
filter paper. Obtain and record the following information in your notebook:
1.
2.
3.
4.
5.
Do not try to determine the melting point for the product. Be sure to locate and
record the reported melting of hexaphenylbenzene.