Synthesis of Tetraphenylcyclopentadienone (TPCPD)
Amanda Reese
CHEM 213
Desk 103C
TA: Anna Powell
April 10, 2014
Reese 2
Introduction
Organic molecules can be altered to perform a variety of practical functions. Dendrimers
are molecules that contain multiple identical branches that can be modified to carry active
compounds. Tetraphenylcyclopentadienone (TPCPD) is a derivative of the highly reactive
cyclopentadienone that has four phenyl groups attached to the main five-membered ring. It is
commonly used as the diene in Diehls-Alder reactions to create dendrimers of pharmacological
and industrial significance. TPCPD is useful not only as a reactant; it is utilized as a cyclone, or a
molecule that binds fine particles so they can be collected. This is specifically useful in food and
drug ingredient synthesis, either to capture impurities or isolate active ingredients from a reaction
mixture1. TPCPD can also be used to synthesize hexaphenylbenzene and pentaphenylbenzene2.
Hexaphenylbenzene has been successfully modified to bind the oligosaccharides found in the
biofilm of the Staphylococcus aureus bacteria3. If the immune system is exposed to these
oligosaccharides on a harmless molecule, it will develop antibodies against them without
suffering disease. Then if the bacteria is encountered it will be quickly destroyer, so the molecule
could act as a vaccine against infection by the specific type of bacteria. The other derivative
mentioned, pentaphenylbenzene, is being tested for its capacity as a hepatocyte growth factor
imitator (HGF)4. HGF is a cell-signaling molecule that promotes organ regeneration by inducing
an inflammatory response. If its imitator succeeds, it could be used to partially block the effects
of HGF and reduce the induced inflammatory response, thereby promoting healing in injured
tissues.
TPCPD is not a naturally occurring molecule, but a product of laboratory synthesis. The
synthesis occurs by the mechanism of a double aldol condensation (depicted in Scheme 1.) This
reaction can be used to form a double bond between an ethylene α-carbon of a ketone and the
Reese 3
carbon of a carbonyl, resulting in an enone product5. The newly formed conjugated system has
nucleophilic character, and several molecules will add into the β-carbon via 1,4 nucleophilic
addition. Some of these include cuprates, cyanides, and amines. Condensation reactions in
general are important in organic chemistry as they allow carbon-carbon double and triple bonds
to form. Alkenes and alkynes are then amenable to undergo several other reactions such as
halogenation or epoxidation.
Scheme 1: Mechanism of the double aldol condensation of benzil and 1,3-diphenylactone to
TPCPD
In the reaction mechanism, the hydroxide acts as a base to deprotonate the α-hydrogen of
the 1,3-diphenylacetone. This allows an enolate intermediate to form. The pi electrons in the
Reese 4
enolate are nucleophilic, so they attack the carbonyl in benzil. The carbonyl pi electrons shift up
to the oxygen, which is then protonated by water. The same α-carbon from the first step is
deprotonated again to form another enolate. This time, the additional lone pair on the oxygen
moves to re-form the carbonyl and the double bond shifts to the adjacent carbon, kicking out
hydroxide. The first condensation is then complete. The 1,3-diphenylacetone’s other α-carbon is
then deprotonated to form another enolate intermediate. The pi electrons from the enolate will
add into benzil’s other carbonyl as the negatively charged oxygen reforms a carbonyl. The
double bond electrons shift to the oxygen, which is then protonated by water. The α-carbon is
deprotonated one final time to reform an enolate that will kick out hydroxide to form a carboncarbon double bond at the alpha position to the ketone.
The purpose of this lab is to make TPCPD by heating 1,3-diphenylbenzene and benzil in
the presence of potassium hydroxide and 95% ethanol. The molecules will undergo a double
aldol condensation to form the final product. The identity of the product will be proven using
melting point, IR, and 1H and 13C NMR data.
Experimental
Benzil (0.4307g, 2.00 mmol), 1,3-diphenylacetone (0.4264g, 2.03 mmol), and 95%
ethanol (5mL) were added to a 25mL round bottom flask and set up to reflux. Reaction was
heated and stirred to homogeneity for 2-3 minutes, then a solution of potassium hydroxide
(0.175g, 3.12 mmol) in 95% ethanol (1.5mL) was added slowly through the condenser. Reflux
continued for 40 minutes afterwards, and was monitored by TLC (2:1 dichloromethane:hexanes.)
The reaction was chilled and the crystals were isolated using a Hirsch funnel and rinsed with
cold 95% ethanol (3x 1mL). Recrystallization (1:1 95% ethanol:toluene) yielded black, shiny
Reese 5
crystals (0.5050g, 81.75%) mp 216-218°C; 1H NMR (60 MHz, CDCl3) δ (ppm) 7.135 (d, 8H),
7.076 (t, 8H), 6.959 (t, 4H); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.2573 (d, 13H), 7.1913 (7,
4H), 6.9344 (d, 4H); 13C NMR (400 MHz, CDCl3) δ (ppm) 200.3473, 154.4554, 133.0122,
130.7091, 130.1277, 129.3206, 128.4967, 128.0244, 127.9704, 127.4450, 125.2690; IR (ATR)
υmax (cm-1) 3055.60, 1704.39, 1597.14, 1487.11.
Results and Discussion
Tetraphenylcyclopentadienone was synthesized through a double aldol condensation of
benzil with 1,3-diphenylacetone. Adding the potassium hydroxide solution provided the base to
deprotonate the α-carbon of the 1,3-diphenylacetone to form an enolate intermediate, which
attacked the electrophilic carbonyl carbon on the benzil. The hydroxide base was reformed to
continue catalyzing the reaction when the carbonyl oxygen was protonated. The heat applied to
the reaction mixture was meant to increase its rate and promote the condensation into a double
bond. Ultimately, a double bond formed between the two carbons, and the mechanism repeated
with the identical other halves of the molecules. Solubility decreases with temperature, so the
reaction mixture was chilled to facilitate the precipitation of TPCPD out of solution. The crude
product was then recrystallized in a 50/50 toluene and 95% ethanol solvent. This solvent mixture
partially dissolves TPCPD at room temperature, but when heated it will dissolve completely. The
purification appeared to be successful, as the melting point was observed to be 216-218 °C, and
the reported melting point of TPCPD is 218-220 °C6. Impurities interfere with molecular
intermolecular forces and consequently lower melting point. As there was minimal melting point
depression, the product did not have high levels of contamination.
Reese 6
The yield of TPCPD from this reaction was 0.6177g, or 80.3%. Of that, 81.75% was
recovered after the purification by recrystallization. The yield was lower than the 91% that has
been reported for this synthesis. The TLC plate ran after 40 minutes of reflux did not show a
benzil or 1,3-diphenylactone spot in the reaction lane, so nearly all of it must have reacted to
form TPCPD. This means that some product must have been lost in transfer as well as
purification. Some of the product stuck to the sides of the flask, but loss of product mainly
occurred in the filtering process, as not all of the TPCPD precipitated out of solution and some
was lost in the filtrate (as was apparent by its dark purple color.) Despite the lower yield, the
spectral data generally suggest that the product obtained was pure.
Table 1: IR peaks of TPCPD
Functional Group
Predicted absorption5 (cm-1)
Observed absorption (cm-1)
Cyclic ketone carbonyl
1750
1704.39
Benzene carbon-carbon
double bond
Benzene carbon-hydrogen
bond
Tetra-substituted carboncarbon double bond
1600, 1580, 1500, 1450
1487.11
3300-3000
3055.60
1670
1597.14
The IR spectra (Figure 1) was not the most useful data in determining the purity of the
TPCPD, as many of the peaks would be observed in both the starting materials and the product.
Benzene rings are present in all three molecules, so the peaks at 3055.60cm-1 and 1487.11cm-1
resulting from aromatic hydrogens and double bonds respectively did not discern if the sample
contained starting material or product. The spectrum displayed a peak at 1597.14cm-1, indicating
the presence of a tetra-substituted carbon double bond that only exists in the TPCPD.
Additionally, there was no peak in the 2960-2850cm-1 region, which would result from the
Reese 7
ethylene groups on 1,3-diphenylacetone. There is a peak at 1704.39cm-1, which lies with in the
carbonyl region, and its lower wavelength of absorption indicates that it is part of a conjugated
system such as that of an enone. Though the IR spectrum suggests that TPCPD was formed, it is
not highly conclusive and needs to be backed up with additional data.
Table 2: 400 MHz 1H NMR peaks of TPCPD
Splitting pattern
Predicted
integral value
Triplet
Predicted
chemical shift
(ppm)5
6.5-8.0
Observed
integral value
4
Observed
chemical shift
(ppm)
6.9344
Triplet
6.5-8.0
8
7.1913
4.308
Doublet
6.5-8.0
8
7.2573
13.07
3.999
The 60 MHz 1H NMR data (Figure 2) supports the positive identification of TPCPD. All
of the peaks were within the range of 6.5-7.5ppm, as would be expected for a compound with
only aromatic hydrogens. At 6.959ppm, a triplet with an integral value of approximately four
was observed, which represents the hydrogens in each phenyl that are farthest from the dienone
ring. The peaks of the other two types of hydrogens, which should take the form of a triplet and a
doublet, had such similar chemical shifts that they overlapped. However, the integral value of 16
matches what would be expected of this molecule. If the starting material 1,3-diphenylacetone
were present, there would be a peak with a shift of about 2.2ppm from its ethylene groups. The
400 MHz NMR spectra (Figure 3) did show a short peak in this range, though it was much
shorter than the peaks from the aromatic hydrogens. The peaks in this spectrum did not have the
exact splitting pattern that would be expected. It shows a doublet with the greatest chemical shift
at 7.2573ppm and a triplet with a shift of 7.1913ppm, which matches what was observed in the
Reese 8
60 MHz. However, the peaks at 6.9344ppm have a pattern that looks more like a doublet than the
anticipated triplet. Additionally, the integral values add up to 21, when there are only 20
hydrogens in TPCPD. These abnormalities could have come from traces of starting materials
whose benzene rings interfered with the scan. The data suggest that, while the sample is mostly
TPCPD, there are some traces of contamination.
The 13C NMR (Figure 4) further confirmed the identity of TPCPD. There are eleven
unique carbons in the molecule, and 11 peaks were observed, not counting the peaks around
77ppm, which result from the solvent CDCl3. The peak with a shift of 200.3473ppm represents
the most deshielded carbon, the one in the carbonyl. The carbons adjacent to the carbonyl are
also more deshielded, and therefore produce a peak with a large chemical shift, 154.4554ppm in
this spectrum. The final type of non-aromatic, alkene carbon has a chemical shift of
125.2690ppm. Aromatic carbon peaks have chemical shifts in the range of 120-160ppm, and the
remaining eight peaks all lie between 127.4450 and 133.0122ppm. There are no peaks in the 1555ppm range, which would indicate the presence of ethylene carbons such as those in 1,3diphenylacetone. There is also an absence of additional peaks in the aromatic and carbonyl
regions, which could mean that benzil was in the sample. So, while there may be traces of
contamination to slightly interfere with the 1H NMR, there is not such a significant amount so as
to appear in the 13C NMR spectra.
The double aldol condensation of benzil and 1,3-diphenylacetone yielded a lower than
average amount of tetraphenylcyclopentadienone, but the purity of the yield was satisfactory.
The integral value and splitting pattern of the 400 MHz 1H NMR were a little off from what was
expected, but the 400 MHz 13C NMR and 60 MHz 1H NMR spectra did not show any significant
contamination. Additionally, the melting point of the sample was only depressed by 2 °C, which
Reese 9
supports the conclusion that the product had minimal contamination. The yield could potentially
be improved by testing a few recrystallization solvents to find one that would dissolve less of the
TPCPD at cold temperatures. As a follow-up experiment, the TPCPD could be modified by
adding new functional groups to the diene, exploiting its utility as a dendrimer precursor. The
synthesis of TPCPD can be accomplished efficiently and effectively, which leaves it as an
attractive candidate for new vaccines and drug delivery systems.
References
1. Salcedo, R.; Paiva, J. Pharmaceuticals: Efficient cyclone systems for fine particle collection.
Filtr. Sep. 2010, 47, 36-9.
2. Dong, Q.; Luo, C.; Zhang, W.; Fan, S.; Zhang, C.; Zhang, H. Synthesis and properties of
hexabenzacoronene derivatives. Huaxue Shiji. 2013, 35, 1073-1076.
3. Weaver, L. G.; Singh, Y.; Vamvounis, G.; Wyatt, M.F.; Burn, P.L.; Blanchfield, J.L.
Carbohydrate globules: molecular asterisk-cored dendrimers for carbohydrate presentation.
Polym. Chem. 2014, 5, 1173-1179.
4. Pillarisetti, S. Small-molecule modulators of hepatocyte growth factor/scatter factor activities
as drugs. US Patent 20,030,045,559, March 6, 2003.
5. McMurry, John. Organic Chemistry, 8th ed.; Brooks/Cole: Belmont, CA, 2008; pp 908-910.
6. Tetraphenylcyclopentadienone; MSDS No. T25801 [Online]; Sigma Aldrich: St. Louis, MO,
Mar 18, 2014.
http://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=US&language=en
&productNumber=T25801&brand=ALDRICH&PageToGoToURL=http%3A%2F%2Fwww.sig
maaldrich.com%2Fcatalog%2Fsearch%3Finterface%3DAll%26term%3Dtetraphenylcyclopentad
ienone%26N%3D0%26focus%3Dproduct%26lang%3Den%26region%3DUS (accessed Mar 22,
2014).