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University of Toronto Scarborough
Lana Mikhaylichenko

The three-step synthesis of the antiepilepsy drug Dilantin Abstract: Dilantin was synthesized in a three-step process involving Benzoin synthesis, oxidation of Benzoin to Benzil and condensation of Benzil with Urea. The melting point range of Dilantin was 290-293 °C and actual yield of 12.5 %. The slightly depressed melting point range indicated some impurities were present. The structures of Benzoin, Benzil and Dilantin were characterized by melting point, mass spectrum, IR 1 and H-NMR spectroscopy to determine the efficiency of the synthetic procedure. Introduction: Epilepsy is the most prevalent neurological disorder, affecting approximately 50 million people worldwide. It results from a temporary electrical disturbance of the brain. Epilepsy is a disorder of the 2 central nervous system characterized by excessive electrical discharge. Atypical seizure may include brief and periodic episodes of change in the normal state of consciousness, loss of muscle tone, and sensory and behavioral alterations. Dilantin is an anticonvulsant which plays an important role in treating patients with epilepsy. Phenytoin (Dilantin), is a well established antiepileptic drug that act through inhibition of brain sodium channels has been chose for its efficacy against partial and generalized 3 seizures. The purpose of this experiment was to synthesize Dilantin from benzaldehyde in three synthetic steps. The first step yielded benzoin from a condensation reaction using benzaldehyde. The second step involved with the oxidation of benzoin to benzil. While the third step occurred through the condensation of Benzil with Urea to produce the final product Dilantin. The products from each step were purified by recrystallization and characterized by melting point, IR and mass spectrum and H-NMR to 1 determine if the desired product is formed. The crude, purified yields and the percent recovery were calculated to determine the efficiency of the synthetic procedure. Results: The reaction mechanisms required to synthesize Dilantin are shown in Figure 1. Benzoin crystals did not formed in the ice bath. However, the IR spectrum of the solution was obtained and the peaks observed did prove Benzoin was found in the solution. Benzoin was obtained from the instructor to proceed to the next step of the experiment. Benzil was synthesized as yellow powder (70% yield, m.p. 90- 93°C). This compound reacted with urea to yield Dilantin. Dilantin was synthesized as a white powder with actual melting point range (290-293 °C) and mass (0.06 g). The percentage yield calculated was 1 12.5 %. Data for IR spectrometry, mass spectrometry, and H-NMR for Benzil, Benzoin and Dilantin are summarized in Table 1. The IR spectrum for crude Benzoin in solution (Figure 7) displayed peaks at 3378.18, 1695.93, -1 1 1583.92 & 1449.73 and 2974.84 cm . The H-NMR for this compound (Figure 4) revealed H 8.0 ppm a (m, 2H), H 7.b8 ppm (m, 1H), H 7.45 ppmc(m, 4H), H 7.32 ppm(t, 2Hd, H 7.24 ppm (t, 1H) andeH f 6.09 ppm (d, 1H). The IR spectrum for crude Benzil (Figure 8) displayed peaks at 1676.86, 1593.46 & -1 1449.05 and 2933.07 cm . The IR spectrum for pure Benzil (Figure 9) revealed peaks at 1677.03, 1577.83 & 1449.05 cm . The mass spectrum of this compound (Figure 2) revealed base peak and 1 molecular ion peak at 105 and 210 m/z respectively. The H-NMR for Benzil (Figure 5) revealed H 7.94 a ppm (m, 4H), H 7.82bppm (m, 2H) and H 7.65 ppm (mc 4H). The IR spectrum for pure Dilantin (Figure 10) displayed peaks at 3192.43, 3031.94, 1717.06, 1597.93 &1493.32 and 1398.09 cm . The mass -1 spectrum of this compound (Figure 3) revealed a base peak and molecular ion peak at 180 and 252 m/z respectively. The H-NMR for Dilantin (Figure 6) revealed H 11.12 ppm (s,aH), H 9.28 ppm (s,1H) andb H c.39 ppm (m,10 H). Discussion: The main goal of this experiment was to synthesize Dilantin in a three-step procedure. Through 1 the use of melting point, mass spectrum, IR and H-NMR spectroscopy, the product’s purity can be evaluated. The yield of Dilantin (0.06g, 12.5 %) was very low compared to the theoretical yield of 0.48 g. Possible reasons can be due to the loss of product while transferring into different containers, during recrystallization or stopping the reaction before it reached 100% completion. Moreover, the actual melting 5 point range of Dilantin was 290-293 °C which is slightly lower than the literature value (286-295 °C). This suggests that impurities were present possibly from trace amounts of starting materials such as urea, 1 Benzil or the solvents. Even the yield was extremely low, the IR and H-NMR analysis are successful in identifying the intermediate and final products formed in each step of the synthesis. The IR for crude Benzoin (Figure 7) showed successful synthesis as it matches with the literature values. The OH group was observed at 3378.18 cm which is very close to the literature value of 3200- -1 4 2 -1 3500 cm . Asp C-H stretch was observed at 2974.48 cm as expected. The presence of benzene ring can be supported by the two peaks at 1583.92 & 1449.73 cm similar to literature values of 1600 & 1450 -1 4 -1 cm . In addition, a C=O stretch at 1695.93 cm was also observed. The presence of these peaks showed that Benzoin was synthesized. Moreover, based on the H-NMR spectra for Benzoin (Figure 4), multiplets were observed at H 8.0 ppm, H 7.58 ppm, and H 7.45 ppm which represent the aromatic protons. a b c The IR for pure Benzil (Figure 8) also showed a quite successful synthesis of the compound. A sp C-H stretch was observed at 2928.04 cm .The presence of benzene ring can be supported by the two -1 -1 peaks at 1577.83 & 1449.05 cm . Moreover, a C=O stretch at 1677.03 cm was also observed. However, a small OH peak at 3405.56 cm was observed unexpectedly. This can be due to the presence of some water molecules and the compound was not completely dried. However, the IR of Benzil should not display any OH peak which highlights the difference from the starting compound Benzoin which contains 1 an OH group. As can be seen from H-NMR spectra for Benzil (Figure 5), multiplets were observed at H a 7.94 ppm, H 7.8b ppm, and H 7.65 ppm chich correspond to the aromatic protons. IR spectra revealed characteristic stretches unique to Dilantin (Figure 10).Asingle broad peak observed at 3192.43 cm indicated the presence of N-H stretch and this value is a bit lower compared to -1 4 the literature value of 3300-3400 cm . Aketone (C=O) on a 5-membered ring stretch was observed at 1717.06 cm . Since the starting products do not contain secondary amine nor ketone on a 5-membered ring, hence, the presence of these peaks did prove Dilantin was formed. In addition, a peak at 1398.09 cm suggested the presence of C-N stretch which is similar to literature value of 1080-1360 cm . -1 4 The mass spectrum (Figure 31 shows the presence of Dilantin with a molecular ion peak at 252 m/z as expected. Based on the H-NMR spectra (Figure 6), a singlet at H (11.12 ppm) and a (9.28 ppm) b represent the protons attached to amide and imide nitrogen respectively. While multiplet occurred at H
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