Introduction:

The purpose of the experiment for week 1 was to synthesize phenytoin (or 5,5diphenylhydantoin) from benzil. The benzil reacts with urea, in a base-promoted
condensation reaction to form the drug, phenytoin. 4,5-diphenyl-2H-imidazol-2-one is a
side product that can be formed during the ring closure step of the mechanism; this
product can be siphoned out of the reaction mixture.
Week 2s reaction also involved drug synthesis, however in this week a test
reaction was performed to evaluate the reaction conditions to modify the aromatic ring of
Fadrozole. In order to examine the reaction, benzonitrile and tert-butanol are used in the
test reaction. The purpose of this experiment was to determine if the Freidel-Crafts
alkylation of benzonitrile is successful or not.
Experimental:
Synthesis of phenytoin: Benzil (0.841 g, 4 mmol) and urea (0.478 g, 7.96 mmol) were
mixed with 95% ethanol (25 mL) in a roundbottom flask. Potassium hydroxide (2.5 mL,
10.5M) was added to this mixture. Then the reaction mixture was heated slowly, and
heated more at reflux for 1.5 hours. The solution was cooled to room temperature and
poured into a beaker of DI water (75 mL). The precipitate was isolated by vacuum
filtered, and the filtrate was treated with CO2 to make the solution acidic. The filtrate was
cooled in an ice bath and the product sample was vacuum filtered. The solid was washed
with ice water, air dried, and recrystallized with 95% ethanol to yield a white, solid
product (.871 g, 87.1% yield): 1H NMR (301 MHz, Chloroform-d) 10.41 (s, 1H), 8.58
(s, 1H), 7.12 (dd, J = 8.0, 1.7 Hz, 4H), 7.07 6.95 (m, 6H).13C NMR (76 MHz,
CHLOROFORM-D) 175.04, 156.76, 139.83, 128.31, 127.92, 126.87, 70.86. IR (NaCl
Plate) 3199 cm-1 R-NH-R & C-H sp2, 2980 cm-1 C-H sp3, 2050-1800 cm-1 Aromatic
overtones, 1713 cm-1 C=O, 1449 cm-1 C=C, 783-696 cm-1 H bending. mp 296.5-298.1 oC.
Synthesis of N-tert-butylbenzamide: Benzonitrile (0.867 g, 8.4 mmol) and 2-methyl-2propanol (.746 g, 10 mmol) were mixed with glacial acetic acid (1.0 mL) in an
Erlenmeyer flask. The solution was magnetically stirred. In a separate flask glacial acetic
acid (1.5 mL) and concentrated sulfuric acid (1.0 mL) were mixed. This solution was
added drop-wise to the reaction mixture. The reaction mixture was magnetically stirred
for 30 minutes. The reaction was quenched with ice-cold water (25 mL). The crude
product was isolated using vacuum filtration, recrystallized with 50% ethanol, and dried
on a vacuum filter to yield a white, gummy product (.828 g, 55.6% yield): 1H NMR (301
MHz, Chloroform-d) 7.69 (dd, J = 7.0, 1.5 Hz, 2H), 7.50 7.38 (m, 1H), 7.38 (td, J =
7.6, 7.0, 1.5 Hz, 2H), 6.02 (s, 1H), 1.45 (s, 9H).13C NMR (76 MHz, Chloroform-d)
167.11, 135.94, 131.18, 128.55, 126.81, 51.70, 28.94. IR (NaCl Plate) 3319 cm-1 R-NHR, 3065 cm-1 C-H sp2, 2965 cm-1 C-H sp3, 1950-1750 cm-1 Aromatic overtones, 1634 cm1
C=O, 693-716 cm-1 Hydrogen bending. GC-MS (HP 5890, 125-300 OC): 4.86 min (53%,
M+: 177). mp 71.9-76.1 oC.

Results and Discussion:

Figure 1 is the IR spectrum of the product, phenytoin, for week 1. There is an
amide (R-NH-R) peak at 3199.70 cm-1, this peak is very large and engulfed the C-H sp2
peak that should be located above 3000 cm-1. There is a C-H sp3 peak at 2980 cm-1,
aromatic overtones from 2050-1800 cm-1, a large C=O peak at 1713 cm-1, a C=C peak at
1449 cm-1, and meta and ortho hydrogen bending peaks in the fingerprint region, from
783-696 cm-1. The starting material would not have the amide (R-NH-R) peak or the CH sp3 peak, which signifies that the starting material was changed into phenytoin during
the course of the experiment. Figure 4 is the IR of the side product. There is an amide
peak at 3222 ppm, a C-H sp2 peak at 3050 ppm, a C-H sp3 peak at 2850 ppm, aromatic
overtones from 2000-1790 ppm, a C=O peak at 1640 ppm, a C=C peak at 1486 ppm, and
ortho and meta H-bending peaks from 765-692 ppm. Figure 4 shouldnt have a C-H sp3,
which means that some impurities were in the side product spectra. The amide peak in
Figure 4 is a lot larger than the one in Figure 1. Figure 2 is the 13C NMR of phenytoin.
There are a total of 7 peaks. Peak A, at 175.04 ppm, corresponds to carbon A, which is a
carbonyl carbon. Peak B, at 156.76 ppm, corresponds to carbon B, which is another
carbonyl carbon in the phenytoin compound. Peak C, at 139.83 ppm, corresponds to the 2
aromatic carbons that are attached to 5-membered, heterocyclic ring. Peak D, at 128.31
ppm, corresponds to the 4 aromatic carbons that are attached to the C carbons. Peak E, at
127.92 ppm, represents 4 aromatic carbons, but these carbons are attached to the D
carbons. Peak F, at 126.87 ppm, represents the 2 aromatic carbons that are located para to
the C carbons. Peak G, at 70.86 ppm, represents carbon G, which is attached to the two
phenyl groups. The 13 C NMR for benzil would only have 5 peaks, due to the symmetry
in the molecule. It would have only one carbonyl carbon peak, and peak G would not be
seen in the 13C NMR of the starting material. Figure 3 is the 1H NMR of phenytoin. There
are 4 main peaks; however there should be 5. Peak A is at 10.41 ppm, is a singlet, has no
neighbors, has an integration of 1.00, and represents hydrogen A, which is attached to one
of the nitrogen atoms. Peak B is at 8.58 ppm, is also a singlet, has no neighbors, has an
integration of 0.99, and represents hydrogen B, which is attached to the other nitrogen
atom in the molecule. Peak C is at 7.52 ppm, is doublet of doublet, has 1 ortho neighbor
and 1 meta neighbor, has J-values of 8.0 and 1.7 Hz, has an integration of 3.81, and

represents the four aromatic hydrogens labeled C. Peak D is from 7.07-6.95 ppm, is
multiplet, has an integration of 5.83 and represents 6 hydrogens. Peak D is an
overlapping peak; there should be 2 separate peaks seen. The first part of peak D should
be a triplet of doublets, to represent the 4 aromatic hydrogens that are attached to the C
hydrogens, have 2 ortho and 1 meta neighbor, and should have J-values between 6.5-8.5
Hz, for the ortho coupling, and 1-3 Hz, for the meta coupling. Toward the end of peak D
there should be a triplet of triplet peaks to represent the two aromatic hydrogens that have
2 ortho and 2 meta neighbors, and have J-values between 6.5-8.5 Hz, for the ortho
coupling, and 1-3 ppm, for the meta coupling. The 1H NMR for benzil would only have 3
peaks for the aromatic hydrogens in the molecule; these peaks would be located more
downfield because they are more deshielded by carbonyl group. There would be no
singlet peaks for the hydrogens attached to the nitrogen atoms, because there are no
nitrogen atoms in the benzil molecule.
The experimental melting point for phenytoin was 296.5-298.1 oC, but the
literature value for the melting point of phenytoin is 293-295 oC. While the product
sample was in the melting point apparatus, some of the sample decomposed rather than
melting; the crystal turned black and began to bubble instead of turning clear. This
decomposition was also observed during the melting of the side product, 4,5-diphenyl2H-imidazol-2-one. The decomposition point of the side product is 310.7-313.4 oC. There
could have been some of the side product still left in the product sample when the melting
point was taken; this would account for the decomposition of one of the product as well
as the higher melting point. The % yield of the product was 87.1%, however due to the
increased melting point of the product sample, some of the product included the sideproduct as well. The 1H NMR also shows that there are impurities in the product sample
because of the Peak D multiplet. Since peak D is an overlapping peak that means there
could be some peaks from the side product within the large multiplet. Since the IR
spectrum of the product had an amide peak, which engulfed that C-H sp2 peak that is a
source of impurity, also the side product spectra seems to have a C-H sp3 even though
there are no sp3 hybridized carbons in the side product. Some sourced of error would be
not bubbling the sample with CO2 long enough or not vacuum filtering long enough. In
order to improve this experiment, the product sample could be vacuum filtered at a

slower rate, or multiple times to ensure that all of the precipitate (side-product) was
removed from the final product sample.
The purpose of week 2s test reaction was to determine if the aromatic ring of a
drug, such as Fadrozole, could be modified via alkylation. Because benzonitrile is very
deactivated, Friedel-Crafts alkylation will not take place. Friedel-Craft reactions do not
occur on deactivated rings; instead another product was made from reacting tert-butanol,
glacial acetic acid, and benzonitrile together. The product formed this week is N-tertbutylbenzamide. Figure 5 is the IR spectra of the product. There is a large amide (R-NHR) peak at 3319 cm-1, a C-H sp2 hybridized peak at 3065 cm-1, a C-H sp3 hybridized peak
at 2965 cm-1, aromatic overtones from 1950-1750 cm-1, a C=O peak at 1634 cm-1, and
ortho and meta hydrogen bending from 693-716 cm-1. The starting material for N-tertbutylbenzamide is benzonitrile. The IR for benzonitrile would not have the R-NH-R
peak, a C=O peak, or a C-H sp3 hybridized peak. The IR from an alkylated benzonitrile
would not have a C=O peak or an amide peak. Because Figure 5 does include these three
peaks, the starting material was reacted to form N-tertbutylbenzamide. Figure 6 is the 13C
NMR of the product. There are a total of 7 peaks to represent a total of 11 carbon atoms.
Peak A, at 167.11 ppm, corresponds to carbon A, which is the carbonyl carbon. Peak B, at
135.94 ppm, corresponds to the aromatic carbon B, which is attached to carbon A. Peak
C, at 131.18 ppm, corresponds to the aromatic carbon para to carbon B. Peak D, at 128.55
ppm, corresponds to the two equivalent carbons that are attached carbon B. Peak E, at
126.81 ppm, corresponds to the two equivalent carbons attached to carbon C. Peak F, at
51.70 ppm, corresponds to carbon F which is attached to the nitrogen atom. Finally peak
G, at 28.94 ppm, corresponds to the three equivalent carbons on the tert-butyl group. The
13

C NMR for benzonitrile would only have 5 peaks because peaks E and F correspond to

sp3 hybridized carbons, which are not found in benzonitrile. Peak A would be located
further up-field in the starting material because carbon A would no longer be attached to
an oxygen atom; it would only be triple bonded to a nitrogen atom. Figure 7 is the 1H
NMR of N-tert-butylbenzamide. Peak A is at 7.69 ppm, has an integration of 1.92, and
corresponds to the two equivalent aromatic hydrogens that are attached to hydrogen C;
its a doublet of doublets, has 1 ortho neighbor and 1 meta neighbor and corresponding Jvalues of 7.0 and 1.5 Hz. Peak B is at 7.50-7.38 ppm, has an integration of 1.21, and

corresponds to aromatic hydrogen B. Hydrogen B is a multiplet in the spectra, but

hydrogen B has two ortho neighbors and two meta neighbors making it a triplet of
triplets, with 2 J-vales in between 6.5-8.5 and two between 1-3 ppm. Peak C is at 7.38
ppm, has an integration of 1.57, and represents the two equivalent aromatic hydrogens
that are attached to hydrogen B; its a triplet of doublets, has 2 ortho neighbors and 1
meta neighbor with corresponding J-vales of 7.6, 7.0, and 1.5 Hz. Peak D is at 6.02 ppm,
has an integration of 0.75, and represents the one hydrogen attached to the nitrogen; it is a
singlet and has no neighbors, and therefore has no J-values. Peak E is at 1.45 ppm, has an
integration of 9.04, and represents the 9 equivalent hydrogens of the tert-butyl group; it is
a singlet and has no J-values. Benzonitrile would not have peaks E and D, because
benzonitrile does not have a tert-butyl group attached and does not have a nitrogen atom
with a hydrogen attached.
Figure 8 is the GCMS of N-tert-butyl-benzamide. There were many little peaks on
the GC, but the main peak had a retention time of 4.86 min and a parent ion of 177.35
M/Z. The parent ion corresponds to the molecular weight of N-tert-butyl-benzamide not
the Friedel-Crafts alkylation product. The % yield of the reaction from the GCMS is
53%; this value is smaller than the calculated % yield of 55.6% because of the multiple
little glacial acetic acid peaks in the GC. Some of the peaks are located before the product
peak; for example at 3.054 min, there is a peak with a M+ of 58, which is very close to the
molecular weight of glacial acetic acid (60 g/mol). There are also peaks after the product
peak. There are peaks at 7.088 min and 8.575 min, that both have parent ions of 58 M/Z,
which is very close to 60 M/Z, which corresponds to the parent ion of glacial acetic acid.
This means there must have been glacial acetic acid in the product sample, which
decreased the experimentally obtained % yield. The crude melting point of the product is
102.9-114.5 oC. The pure experimental melting point of N-tert-butylbenzamide is 120125.1 oC, but the literature value for the melting point of the product is 133-135 oC. The
experimental melting point is lower than the literature value because impurities from the
acetic acid, or other compounds, disrupt the crystal lattice structure of the product and
make the crystals easier to melt. The pure melting point was higher than the crude
because there were less impurities in the pure sample. In Figure 5 the amide peak is very
large, so there could be hydroxyl groups present in the product sample, which would give

such a large peak. In Figure 7, peak B is a multiplet, so there could be other peaks
overlapped within the peak that would make the multiplicity less distinct. Some sources
of error in this experiment could be adding the glacial acetic acid and sulfuric acid
mixture too quickly and not vacuum filtering enough. In order to improve the experiment
the final product could be vacuum filtered longer, and the acid mixture could be added
using a separatory funnel to ensure a slow, drop-wise, constant addition to the reaction
mixture.