Synthesis of Dilantin
Introduction:
Dilantin is commonly used to treat epilepsy. It is an enzyme inducing drug that helps
metabolize other anticonvulsant drugs in the body which slows impulses in the brain that causes
seizures.1 Dilantin reacts with many other drugs because it has some very unique properties. It is
loosely bounded to plasma proteins, and largely metabolized by cytochrome enzymes. Since it is
loosely bound to these enzymes and proteins, the occurrence of inhibition and metabolism with
other drugs is frequent. The main mechanism of dilantin is inhibiting collagenase. This is very
useful when treating skin related diseases and injuries. A specific example of the effect of
dilantin on a cellular level is examining patients with epidermolysis bullosa. People who suffer
from this disease have an increased level of collagenase which removes polysaccharides from the
connective tissue and increases blistering.2 By inhibiting collagenase with dilantin, blistering of
the skin decreases. Additionally, dilantin is known to increase the expression of growth factor B
in macrophages which promotes the healing of ulcers and traumatic wounds.2 Dilantin has many
different uses and can treat a variety of diseases which makes it a very essential drug in the
medical field.
Dilantin is synthesized by a condensation reaction between urea and benzil which is also
known as the Bilitz synthesis. This experiment uses a modified version of the traditional
condensation reactions because the yields are not as high as they should be. The first step in the
reaction is addition of the urea anion to benzil which rearranges in a fashion similar to a
benzilbenzilic rearrangement.3 Next, the oxygen group becomes protonated by water and leaves
behind a base in solution. This base is protonated by the proton of the secondary amine and
water is reformed. Electron shifts occur and the hydroxyl group is lost. This hydroxyl group
deprotonates the primary amine and causes cyclization. Finally, the benzylic rearrangement
occurs which completes the synthesis of Dilantin.
Dilantin can be synthesized by a condensation reaction which is a technique that is
readily used in organic chemistry. A condensation reaction is when 2 or more molecules
combine to form a larger structure with a loss of a smaller molecule such as water. There are
many types of condensation reactions: aldol, claisen, carbonyl, dieckmann, and even
polymerization. Many important drugs and materials are synthesized by this reaction which
makes it an essential technique in organic chemistry.
The purpose of this experiment is to synthesize dilantin from benzil and urea via a
condensation reaction. The crude product will then be purified by recrystallization. The success
of the experiment will be determined by calculating a percent yield, determining the melting
point, and analyzing the final product by IR, 60 MHz 1H NMR, 400 1H NMR, and 400 MHz
13C NMR.
Experimental:
Benzil (400 mg), absolute ethanol (6 mL), 30% aqueous sodium hydroxide (1.5 mL), and
urea (200 mg) was refluxed for 2 hours. This reaction was monitored every 30 minutes by TLC.
Once completed, the mixture was cooled and poured into distilled water (10 mL). It was then
acidified drop wise using glacial acetic acid. Once acidity was determined by pH paper, it was
placed on ice (15 mins) and collected via vacuum filtration. The product was then purified by
recrystallization (95% ethanol); 1H NMR (400 MHz, DMSO) δ (ppm) 7.3471-7.4035 (m, 10H),
9.3397(s, 1H), 11 (m, 1H); 13C NMR (400 MHz, DMSO) δ (ppm) 38.6913-39.9435, 126.4583,
127.9442, 128.4149, 155.9083; IR (ATR) v max (cm-1) 1491.88, 1679.06, 1770.43, 2108.06.
Results and Discussion:
The synthesis of dilantin was done by a condensation reaction. Urea and Benzil were
combined together to for a denser compound. The high pressure in the condenser allows the
starting materials to come together and form the desired product. This reaction was done in an
alkaline solvent, and the presence of sodium hydroxide allowed a phenyl shift to occur. This
reaction was monitored by TLC. Dilantin is much more polar that benzil and therefore eluted
faster in the nonpolar mobile phase. Once there was no evidence of starting material, the
reaction was stopped and acidified to protonate the alkene to yield the final product.
From the 0.4 grams of benzil, 0.505 grams of Dilantin is theoretically supposed to be
produced. Before recrystallization, 0.3950 grams of Dilantin was collected. However, after the
purification some product was lost. 0.3028 grams was the final weight of the recovered product
which makes the percent recover 77% and the percent yield 60%. This exceeded the percent
yield in a typical traditional synthesis (55%), but is not as high as it should be in the Bilitz
synthesis. This may have been from product being melted during the process of recrystallization.
The melting point of the final product was also determined to analyze the success of the reaction.
Dilantin has a high melting point of 293-295°C, and benzil has a significantly lower melting
point of 94-95°C. The observed melting point was higher than 150 degrees Celsius but could not
be determined directly because it surpassed the thermometers maximum temperature reading.
However, since the product did not melt at 94-95°C, it can be concluded that benzil was not
present.
This product was analyzed by IR spectra. The major change that should have been
observed was the transformation of a carbonyl group into cyclopentanone and the addition of
amines. The amine was a weak signal at 1491.88 cm-1, and the cyclopentanone was a strong
sharp signal at 1770.43 cm-1. Since there was no presence of a peak at 1715 cm-1, this indicated
that carbonyl groups were not present from the starting material benzil. This spectrum also
shows the presence of the benzene ring double bonds at 1679.06 cm-1, and the benzene
hydrogens at 3208.06 cm-1. The presence of these particular peaks does characterize dilantin and
therefore can be concluded that the reaction did proceed as planned.
1
H NMR 60 MHz was not very helpful in characterizing the product. Therefore the
product was analyzed by 1H NMR 400 MHz because it is more sensitive and can show the peaks
more clearly. There was a large water impurity at 3.443 ppm that may have been in the tube
prior to adding the sample, and a peak at around 2.5 which represents the DMSO solvent and can
be ignored. The multiple peaks around the 7 ppm zone represent the 10 aryl hydrogens. This
does not differ from bezil, but can still be used to confirm Dilantin is present. Additionally, the
peaks at 9.3397 ppm and 11 ppm represent the 2 amide protons. No amide protons are present in
benzil so this shows that the reaction did go to completion.
13
C NMR was also useful in characterizing the final product. There is a peak at 155.9083
ppm which represents the carbonyl group, peaks around 127 ppm which represent the phenyl
carbons, and a peak at 70.1062 ppm which represents the tetrasubstituted carbons. There are 7
distinct carbon peaks the 39 ppm range. This indicates that Dilantin is in fact present and not
benzil because benzil only has 5 distinct carbons.
Overall, the data from this experiment showed that the desired product was synthesized
by a successful condensation reaction. The IR, H NMR, and C NMR data characterized dilantin,
and the melting point and percent yield further supported the synthesis of the product. There
were a few minor impurities that could be fixed by being more careful while preparing the NMR
samples.
References:
1. J. Chem. Educ., 1983, 60 (6), p 512
2. The Journal of Investigative Dermatology (1951) 16, 43–52; doi:10.1038/jid.1951.6
3. J. Chem. Educ., 1986, 63 (7), p 650