Experiment V: Multistep Convergent Synthesis: Synthesis
of Hexaphenylbenzene
1) Introduction
CHO
O
OH
Thiamine HCl (V-02)
NaOH (aq)
Ph
Ph
Cu(OAc)2
NH4NO3
HOAc
Ph
Ph
O
O
V-01
V-03
V-04
O
Ph
Ph
NMe3+OH-
Ph
V-06
V-05
Ph
O
Ph
Tetraphenylcyclopentadieneone
Ph
Ph
V-07
Br
Ph
Ph
+
-
nBu4N Br3
V-09
Ph
Ph
Br
V-08
V-10
KOH
Ph
Ph
Diphenylacetylene
V-11
O
Ph
O
Ph
Ph
+
Ph
Ph
Ph
Ph
Ph
V-07
Ph
Ph
Ph
Ph
V-11
+
CO (g)
V-12
The conversion of benzaldehyde (V-01) to benzoin (V-03) is generally known as the
typical benzoin condensation. The traditional reaction conditions for such a condensation
take the advantage of cyanide anions which act as a good nucleophile on the aldehyde
moiety. However, such a reagent is of course very toxic and should be avoided as much
as possible. A quite similar type and less toxic reagent is thiamine hydrochloride (V-02).
Step 2 is a simple and very mild redox reaction of V-03 to benzil (V-04) in which
copper(II) is reduced to copper(I) and nitrogen gas is evolved. The reaction between V-04
and carbonyl compound V-05 in the presence of a base is a double aldol condensation
with elimination of two equivalents of water to give enone V-07.
The other parallel synthesis toward V-12 involves the preparation of diphenylacetylene
(V-11). Thus, the addition and subsequent elimination sequence starting with transstilbene yields V-08. Instead of using neat bromine in the reaction from V-08 to V-10, a
much milder bromination reagent (V-09) is used here.
The last step is a Diels Alder reaction between diphenylacetylene (V-11) and
tetraphenylcyclopentadienone (V-07) with loss of CO to give hexaphenylbenzene (V-12).
2) Synthetic Procedures
2.1 Synthesis of Benzoin (V-03)
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 α-hydroxyketones (acyloins). The related compound thiamine
hydrochloride (V-02) 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
N
H
S
O
Cl
+
N
N
O
O P O P O
OH
H
HCl
S
OH
OH
Thiamine Pyrophosphate
Thiamine Hydrochloride
(V-02)
Procedure:
CHO
OH
Thiamine HCl (V-02)
NaOH (aq)
Ph
Ph
O
V-01
V-03
Add thiamine hydrochloride (V-02), (750 mg) to a suitable round bottom flask. Dissolve
the solid in water (2.5 mL) by swirling, add 95% ethanol (7.5 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 vial and add benzaldehyde (V-01), (4.5 mL). Reweigh the
vial and determine the exact mass of the benzaldehyde added. Attach an air condenser
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 on a Hirsch funnel by vacuum filtration and wash the crystals
with two 5 mL portions of ice cooled water. Weigh the dry crude product, determine the
melting point and calculate the yield. The benzoin obtained should be of sufficient purity
to continue the next step. However, if the melting point is more than 5°C off the literature
value, the product should be purified by recrystallization from 95% ethanol by using ~ 8
mL of ethanol per gram of benzoin. Obtain and record the following information in your
notebook:
1.
2.
3.
4.
5.
6.
7.
purified product description (color, physical state, etc.)
purified product weight/yield
TLC analysis
melting point
IR of product (V-03) (interpret)
H1 NMR of the starting material (V-01) (interpret)
C13 NMR of the starting material (V-01) (interpret)
2.2 Synthesis of Benzil (V-04)
O
OH
Ph
Ph
O
V-03
Cu(OAc)2
NH4NO3
HOAc
Ph
Ph
O
V-04
Dissolve cupric acetate (10 mg) and ammonium nitrate (500 mg) in deionized water (750
µL) and glacial acetic acid (2.8 mL) in a 10 mL round bottom flask containing a suitable
stir bar. Attach a reflux condenser and slowly heat the flask if the salts are difficult to
dissolve. As the reaction will evolve nitrogen gas, it is very important to keep the reaction
apparatus open to the atmosphere at all times. Once a homogenous solution is obtained,
cool the reaction flask to ambient temperature. Add benzoin (V-03, 1.00 g) to the stirred
solution at room temperature, attach the condenser and start heating the mixture gently.
Reflux the reaction mixture for 1 hr and the benzoin reaction mixture will become more
homogenous and green. About 100 mL of nitrogen gas will evolve during this time!!
Cool the reaction to ambient temperature and add water (5 mL). Cool the reaction flask in
an ice/water bath around 10 minutes and collect the yellow crystals of benzil (V-04)
using a Hirsch funnel. Wash the crystals with two portions of cooled water (10 mL). The
benzil obtained often contain small amounts of unreacted benzoin. Take a TLC on the
crude crystals using methylene chloride as the eluent. Recrystallize the crude material
from methanol and perform another TLC analysis. The crude material of benzil can also
be purified using column chromatography. It is very important that the benzil (V-04)
obtained in this step is free from benzoin (V-03) 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 autooxidation product of benzoin). 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.
purified product description (color, physical state, etc.)
purified product weight/yield
TLC analysis
melting point
IR (interpret)
2.3 Synthesis of Tetraphenylcyclopentadienone (TPCPD) (V-07)
O
O
Ph
O
V-05
Ph
O
Ph
Ph
Ph
V-04
Ph
Ph
NMe3+OHV-06
Ph
Ph
V-07
Combine the purified benzil (V-04, 300 mg) obtained from the previous step with 1,3diphenylacetone (V-05, 300 mg) and triethylene glycol (1.5 mL) in a 10 mL round
bottom flask containing a stir bar. Attach an air condenser and heat the reaction at 135145 °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 µL of a 40% benzyltrimethylammonium
hydroxide (V-06) solution in methanol is cautiously added with stirring (do this in the
hood!). Allow the reaction mixture to cool to room temperature. While the reaction
mixture is cooled, dark purple crystals of tetraphenylcyclopentadienone (V-07) 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 using a Hirsch funnel 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.
7.
purified product description (color, physical state, etc.)
purified product weight/yield
TLC analysis
melting point
IR of product (V-07) (interpret)
H1 NMR of the reagent (V-05) (interpret)
C13 NMR of the reagent (V-05) (interpret)
2.4 Synthesis of meso-stilbene dibromide (V-10)
Br
Ph
Ph
nBu4N+Br3V-09
Ph
Ph
Br
V-08
V-10
Transfer trans-stilbene (V-08) (6 mmole) and methylene chloride (20 mL) to a 50 mL
Erlenmeyer flask and cool the contents to 0oC in an ice water bath. Use a powder funnel
to add tetrabutyl ammonium tribromide (V-09) (6.5 mmoles) to the reaction contents.
Wash any tetrabutyl ammonium tribromide adhering to the inside of the flask with
additional methylene chloride (5 mL). Remove the ice water bath and allow the reaction
to gradually warm to room temperature. Be sure to cover the reaction vessel to prevent
methylene chloride vapors from escaping (methylene chloride is quite volatile and
hazardous!). Stir the reaction contents for an additional 45 minutes. During this time, the
orange colored solution gradually changes to yellow. If time permits, a longer reaction
time will result in better yields. You may set the reaction contents aside until the next
laboratory period. If you do this, be sure to cover the flask securely so that the methylene
chloride does not evaporate (hazardous vapors!).
Filter the crystalline product from the reaction mixture by vacuum filtration using a Hirsh
funnel. Wash the product with three portions of cold water (10 mL each) and then with
two portions of 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.
crude product description (color, physical state, etc.)
crude weight/yield
TLC analysis
melting point
IR
2.5 Synthesis of Diphenylacetylene (DPA) (V-11)
Br
Ph
Ph
Br
V-10
KOH
Ph
Ph
Diphenylacetylene
V-11
Transfer meso-stilbene dibromide (V-10, 800 mg) and KOH (800 mg) to a 25 mL
Erlenmeyer flask containing a stir bar. Add triethylene glycol (4 mL) and heat the
reaction mixture at 195oC for 10 minutes. 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. Wash the crystals with cooled 70% ethanol (2 x
1 mL) and let them air dry on a filter paper. Obtain and record the following information
in your notebook:
1.
2.
3.
4.
5.
crude product description (color, physical state, etc.)
crude weight/yield
TLC analysis
melting point
IR
2.6 Synthesis of Hexaphenylbenzene (V-12)
Ph
Ph
O
Ph
Ph
+
Ph
Ph
Ph
Ph
Ph
Ph
V-07
Ph
Ph
V-11
+
CO (g)
V-12
Add tetraphenylcyclopentadienone (V-07, 100 mg), diphenylacetylene (V-11, 100 mg)
and high-boiling silicon oil (2 mL) to a 13 x 100-mm disposable test tube. Clamp the test
tube in an angle facing the opening away from all personnel. Heat the reaction mixture
gently using a Bunsen burner and boil the mixture for 5 minutes. Make sure to remove
all sources of solvents and perform this experiment in an assigned area in a “solvent
free” hood. All reagents will dissolve in the hot silicon oil and a dark purple solution will
be obtained. Continue boiling the reaction mixture for an additional 10 minutes and the
product starts to crystallize as tan crystals. Cool the test tube at room temperature and add
hexane (4 mL). Mix on a Vortex mixer and crude product (V-12) is collected by vacuum
filtration using a Hirsch funnel. Wash the crystals with hexane (2 mL) and next with
cooled 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.
product description (color, physical state, etc.)
weight/yield
TLC analysis
literature value for melting point
IR
Do not try to determine the melting point for the product. Be sure to locate and
record the reported melting of hexaphenylbenzene.