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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 2’s 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.
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) δ 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) δ 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) δ 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) δ
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.

It would have only one carbonyl carbon peak.52 ppm. but these carbons are attached to the D carbons. Peak A. and ortho and meta H-bending peaks from 765-692 ppm. which is a carbonyl carbon. at 126. represents 4 aromatic carbons. a C-H sp3 peak at 2850 ppm. is doublet of doublet. at 70. at 139. at 127.76 ppm.7 Hz.87 ppm. which is attached to the other nitrogen atom in the molecule.0 and 1. which means that some impurities were in the side product spectra.Results and Discussion: Figure 1 is the IR spectrum of the product. Figure 4 is the IR of the side product. phenytoin. which is attached to the two phenyl groups. a C=C peak at 1449 cm-1. at 128.92 ppm. at 175. The amide peak in Figure 4 is a lot larger than the one in Figure 1. Figure 4 shouldn’t have a C-H sp3. and meta and ortho hydrogen bending peaks in the fingerprint region. has no neighbors. due to the symmetry in the molecule. a C=C peak at 1486 ppm. represents carbon G.70 cm-1. and .41 ppm. Peak A is at 10. Peak B. corresponds to the 2 aromatic carbons that are attached to 5-membered. this peak is very large and engulfed the C-H sp2 peak that should be located above 3000 cm-1. and represents hydrogen B.58 ppm. has an integration of 1. corresponds to the 4 aromatic carbons that are attached to the C carbons.81. has an integration of 3.83 ppm.04 ppm. Peak B is at 8. has 1 ortho neighbor and 1 meta neighbor. There are a total of 7 peaks. has J-values of 8. The starting material would not have the amide (R-NH-R’) peak or the CH sp3 peak. Peak C is at 7. Peak C.31 ppm. and represents hydrogen A. is also a singlet. heterocyclic ring.00. for week 1.86 ppm. a C-H sp2 peak at 3050 ppm. and peak G would not be seen in the 13C NMR of the starting material. Peak E. Peak D. The 13 C NMR for benzil would only have 5 peaks. Figure 2 is the 13C NMR of phenytoin. corresponds to carbon A. at 156. Peak F. a large C=O peak at 1713 cm-1. however there should be 5.99. aromatic overtones from 2050-1800 cm-1. There are 4 main peaks. There is an amide (R-NH-R’) peak at 3199. There is a C-H sp3 peak at 2980 cm-1. from 783-696 cm-1. a C=O peak at 1640 ppm. Peak G. has an integration of 0. aromatic overtones from 2000-1790 ppm. is a singlet. has no neighbors. corresponds to carbon B. represents the 2 aromatic carbons that are located para to the C carbons. which is attached to one of the nitrogen atoms. Figure 3 is the 1H NMR of phenytoin. which is another carbonyl carbon in the phenytoin compound. There is an amide peak at 3222 ppm. which signifies that the starting material was changed into phenytoin during the course of the experiment.

There could have been some of the side product still left in the product sample when the melting point was taken. some of the sample decomposed rather than melting. Since peak D is an overlapping peak that means there could be some peaks from the side product within the large multiplet.5-8. Peak D is from 7.5-diphenyl2H-imidazol-2-one. This decomposition was also observed during the melting of the side product. for the meta coupling. Peak D is an overlapping peak. to represent the 4 aromatic hydrogens that are attached to the C hydrogens. however due to the increased melting point of the product sample. 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. for the ortho coupling. for the ortho coupling. 4. have 2 ortho and 1 meta neighbor. the crystal turned black and began to bubble instead of turning clear. The % yield of the product was 87. for the meta coupling.1 oC. is multiplet. In order to improve this experiment.07-6. The experimental melting point for phenytoin was 296. While the product sample was in the melting point apparatus. The 1H NMR for benzil would only have 3 peaks for the aromatic hydrogens in the molecule. The decomposition point of the side product is 310. has an integration of 5. also the side product spectra seems to have a C-H sp3 even though there are no sp3 hybridized carbons in the side product.1%. which engulfed that C-H sp2 peak that is a source of impurity. There would be no singlet peaks for the hydrogens attached to the nitrogen atoms.95 ppm. the product sample could be vacuum filtered at a .5-8.5 Hz. The first part of peak D should be a triplet of doublets.7-313. Since the IR spectrum of the product had an amide peak. and should have J-values between 6. The 1H NMR also shows that there are impurities in the product sample because of the Peak D multiplet.5-298.4 oC. and 1-3 ppm.represents the four aromatic hydrogens labeled C. Some sourced of error would be not bubbling the sample with CO2 long enough or not vacuum filtering long enough. there should be 2 separate peaks seen.5 Hz. this would account for the decomposition of one of the product as well as the higher melting point. and 1-3 Hz. because there are no nitrogen atoms in the benzil molecule. these peaks would be located more downfield because they are more deshielded by carbonyl group. and have J-values between 6. but the literature value for the melting point of phenytoin is 293-295 oC.83 and represents 6 hydrogens. some of the product included the sideproduct as well.

The purpose of week 2’s test reaction was to determine if the aromatic ring of a drug. Peak B. at 28. which are not found in benzonitrile. corresponds to the two equivalent carbons that are attached carbon B. it’s a doublet of doublets.11 ppm.70 ppm. such as Fadrozole. Friedel-Crafts alkylation will not take place. The 13 C NMR for benzonitrile would only have 5 peaks because peaks E and F correspond to sp3 hybridized carbons. Figure 7 is the 1H NMR of N-tert-butylbenzamide. corresponds to carbon F which is attached to the nitrogen atom. corresponds to the two equivalent carbons attached to carbon C. Friedel-Craft reactions do not occur on deactivated rings. a C-H sp2 hybridized peak at 3065 cm-1. at 135. and corresponds to the two equivalent aromatic hydrogens that are attached to hydrogen C.94 ppm. the starting material was reacted to form N-tertbutylbenzamide. Peak D. has an integration of 1.94 ppm.50-7. at 128. The IR from an alkylated benzonitrile would not have a C=O peak or an amide peak.55 ppm. which is attached to carbon A.18 ppm. Peak F.38 ppm. Because Figure 5 does include these three peaks. and .21. and benzonitrile together. corresponds to the three equivalent carbons on the tert-butyl group. Peak A is at 7. There is a large amide (R-NHR’) peak at 3319 cm-1. at 126. or multiple times to ensure that all of the precipitate (side-product) was removed from the final product sample. Figure 5 is the IR spectra of the product. which is the carbonyl carbon. Peak A would be located further up-field in the starting material because carbon A would no longer be attached to an oxygen atom.0 and 1. Finally peak G. glacial acetic acid. instead another product was made from reacting tert-butanol. a C=O peak at 1634 cm-1.69 ppm. Peak B is at 7. and ortho and meta hydrogen bending from 693-716 cm-1.5 Hz. Because benzonitrile is very deactivated. it would only be triple bonded to a nitrogen atom. a C-H sp3 hybridized peak at 2965 cm-1. at 51.81 ppm. aromatic overtones from 1950-1750 cm-1. Peak E. a C=O peak. Figure 6 is the 13C NMR of the product. could be modified via alkylation. Peak C. at 131. corresponds to carbon A. corresponds to the aromatic carbon B. has 1 ortho neighbor and 1 meta neighbor and corresponding Jvalues of 7. The IR for benzonitrile would not have the R-NH-R’ peak.slower rate. The product formed this week is N-tertbutylbenzamide. corresponds to the aromatic carbon para to carbon B. Peak A.92. There are a total of 7 peaks to represent a total of 11 carbon atoms. has an integration of 1. or a C-H sp3 hybridized peak. at 167. The starting material for N-tertbutylbenzamide is benzonitrile.

The experimental melting point is lower than the literature value because impurities from the acetic acid. and 1. has an integration of 9. for example at 3. The pure melting point was higher than the crude because there were less impurities in the pure sample.5 and two between 1-3 ppm. which would give . but hydrogen B has two ortho neighbors and two meta neighbors making it a triplet of triplets. Figure 8 is the GCMS of N-tert-butyl-benzamide.6% because of the multiple little glacial acetic acid peaks in the GC.9-114. there is a peak with a M+ of 58.5 oC. which is very close to 60 M/Z. Some of the peaks are located before the product peak. There are also peaks after the product peak. which is very close to the molecular weight of glacial acetic acid (60 g/mol). There were many little peaks on the GC.86 min and a parent ion of 177. Benzonitrile would not have peaks E and D. with 2 J-vales in between 6.6.5-8. and represents the 9 equivalent hydrogens of the tert-butyl group. The pure experimental melting point of N-tert-butylbenzamide is 120125. and therefore has no J-values.054 min. The % yield of the reaction from the GCMS is 53%.02 ppm. There are peaks at 7. and represents the one hydrogen attached to the nitrogen.35 M/Z. In Figure 5 the amide peak is very large.0. and represents the two equivalent aromatic hydrogens that are attached to hydrogen B. or other compounds. it’s a triplet of doublets. The parent ion corresponds to the molecular weight of N-tert-butyl-benzamide not the Friedel-Crafts alkylation product. it is a singlet and has no J-values. it is a singlet and has no neighbors.5 Hz. Hydrogen B is a multiplet in the spectra.088 min and 8.04. that both have parent ions of 58 M/Z. but the literature value for the melting point of the product is 133-135 oC. Peak E is at 1.75. this value is smaller than the calculated % yield of 55.45 ppm. The crude melting point of the product is 102. This means there must have been glacial acetic acid in the product sample. disrupt the crystal lattice structure of the product and make the crystals easier to melt. which decreased the experimentally obtained % yield. Peak D is at 6. because benzonitrile does not have a tert-butyl group attached and does not have a nitrogen atom with a hydrogen attached.57. has an integration of 0.575 min. 7. has an integration of 1.corresponds to aromatic hydrogen B.1 oC. Peak C is at 7.38 ppm. which corresponds to the parent ion of glacial acetic acid. so there could be hydroxyl groups present in the product sample. has 2 ortho neighbors and 1 meta neighbor with corresponding J-vales of 7. but the main peak had a retention time of 4.

. so there could be other peaks overlapped within the peak that would make the multiplicity less distinct. peak B is a multiplet. In Figure 7.such a large peak. 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. drop-wise. and the acid mixture could be added using a separatory funnel to ensure a slow. constant addition to the reaction mixture. In order to improve the experiment the final product could be vacuum filtered longer.