Multiple Synthesis - Lab Report Example

The multistep synthesis of phenytoin from benzaldehyde Summary: This experiment involved the three-step synthesis of phenytoin starting from benzaldehyde. Benzoin, synthesized from benzaldehyde was used to form benzil, which in turn was reacted with urea in sodium hydroxide to form phenytoin. The weight of benzil formed (3.307 grams), its % yield (82.675%) and the weight of phenytoin formed (0.068 grams) were determined successfully. Examination of the phenytoin formed proved that the experiment was successful, despite the fact that there were a few experimental errors made. Introduction: Phenytoin is a popular anticonvulsant used in the treatment of epileptic seizures. It also has muscle relaxing and anti-arrhythmic properties (Genome Alberta and Genome Canada). It was first synthesized in 1887, but its structure was determined in 1908 by a German physician, Heinrich Biltz (Gbaguidi, Kapanda and Lambert). The Biltz’s process of synthesizing phenytoin involves several steps, with each step forming a product that will be used in the next step. The process starts with the synthesis of benzil from benzoin, which then undergoes condensation catalysis by a base with urea. Synthesis of benzoin occurs by the thiamine-catalyzed condensation of two molecules of benzaldehyde: Benzoin is then reacted with concentrated nitric acid to form benzil: Benzil then reacts with urea in the presence of a base to form phenytoin: The multistep synthesis of various natural products, most of which are used as medicine, is necessary because of the lack of naturally occurring starting materials, and also because of the reason that multistep synthesis allows for the modification of various functional groups in the medicine, thus improving efficiency. Experimental: a. Synthesis of benzoin 1.3 grams of thiamine hydrochloride were dissolved in 4.0 mL of distilled water in a 50 mL Erlenmeyer flask. 1.5 mL of 95% ethanol was added to the flask and the mixture cooled in an ice water bath. 2.5 mL of 3.0M sodium hydroxide was added dropwise to the solution while swirling. The temperature of the reaction system was maintained at below 20⁰C. While swirling the flask, 7.5 mL of benzaldehyde was added to the flask and the mixture heated in a water bath at 50⁰C for ten minutes. The flask was labeled and covered with a Parafilm® and then placed in a fume hood for one week. The inside of the flask was gently scratched with a glass stir rod to induce crystallization. Since no crystals formed, the stir rod was dipped into the liquid and removed, and then allowed to dry in air. The flask was placed in a water bath with a temperature of 60⁰C to evaporate off some ethanol and then cooled in an ice bath. The color of the solution was noted down. An infrared spectrum of the benzoin sample provided was taken, and the sample used in the next step. b. Synthesis of benzil 4.00 grams of the benzoin provided were added to a 125 mL Erlenmeyer flask. The mixture was heated in a water bath in a fume hood until the mixture stopped producing brown-colored gas. The flask was then removed from the water bath and then 75.0 mL of distilled water added to the mixture. The mixture was allowed to cool to room temperature. While it was cooling, the flask was swirled for two minutes so as to coagulate the precipitate formed. The product formed was isolated by vacuum filtration. The yellow solid formed was then washed with 100 mL of cold distilled water. The solid was then pressed gently on a smooth, hard surface to get rid of excess water. The crude product formed was dissolved in a small amount of hot 95% ethanol. Small amounts of water were added to the hot ethanol until the solution began turning cloudy. The cloudy solution was heated until it became clear again, after which it was slowly cooled to room temperature. Further cooling was done on an ice bath. The purified benzil was then isolated by vacuum filtration and the solid dried. 0.5 mg of the recrystallized benzil was dissolved in 0.5 mL of 95% ethanol in a test tube. One drop of 3.0M sodium hydroxide was added to the solution. The lack of colour change was noted. Additionally, a small amount of benzoin was added to the test tube and the color change observed. The solid formed was then allowed to dry for one week after which the actual yield, % yield and melting point were determined. An infrared spectrum of the benzil formed was taken. c. Synthesis of phenytoin 2.00 grams of benzil formed above and 0.96 grams of urea were dissolved in 50.0 mL of 95% ethanol in a 50 mL round-bottomed flask. 1.8 grams of sodium hydroxide were dissolved in 6.0 mL of water in a small beaker. After complete dissolution of both mixtures, the sodium hydroxide solution was added to the benzil solution. The color change was noted down. The solution formed was refluxed for one and a half hours. After refluxing, the solution was allowed to cool to the point where it was warm to the touch. 25 mL of cool, distilled water was added to the mixture. Using a small plug of glass wool placed on a glass funnel, the mixture was filtered. Concentrated hydrochloric acid was added to the filtrate until the solution turned acidic and crystals had stopped forming. pH paper was used to determine the acidity in this step. The product formed was isolated by vacuum filtration. The isolated product was washed using ice cold water. The phenytoin obtained was then recrystallized in 95% ethanol after which it was isolated by use of vacuum filtration. The product formed was then dried in an oven. The mass, crystalline form and color of the product were determined. An infrared spectrum of the final product was taken. Results: During the synthesis of benzoin, a yellow solution formed. The infrared spectrum of the benzoin sample provided was: Figure 1: Infrared spectrum of benzoin In the synthesis of benzil, there was no color change when recrystallized benzil was dissolved in 95% ethanol and a drop of 3.0M sodium hydroxide added. The melting point was measured and found to be between 84⁰C-86⁰C. The weight was 3.307 grams. The % yield is: % yield = (3.307/4.000) x 100 % yield = 82.675% The infrared spectrum taken was: Figure 2: Infrared spectrum of benzil During the synthesis of phenytoin, a red solution was formed when sodium hydroxide was added to the mixture containing benzil and urea. The phenytoin formed weighed 0.068 grams and had a light yellow color with a soft and fluffy appearance. The infrared spectrum taken was: Figure 3: Infrared spectrum of phenytoin Discussion: The –OH group in sodium hydroxide deprotonates the thiamine as per the mechanism below: Figure 4: Mechanism of deprotonation of thiamine (Univesite De Geneve) The benzaldehyde that was added to the flask was attacked by the deprotonated thiamine as per the mechanism below: Figure 5: Mechanism of formation of benzil from benzaldehyde (Univesite De Geneve) A benzoin sample was provided because it was not possible for crystals to form during the synthesis of benzoin because of heating to evaporate the excess ethanol. The benzil undergoes a series of reactions with urea and the hydroxide group on sodium hydroxide to form phenytoin as illustrated below: Figure 6: Mechanism of formation of phenytoin from benzil and urea (Koreeda). It was not possible to crystallize the benzoin formed in the first step because the heating used to evaporate the excess ethanol might have also evaporated some of the benzoin formed. The melting point of the benzil was at 84⁰C-86⁰C. This differs from the literature value of 94⁰C-95⁰C (Sigma-Aldrich). The huge difference was most likely due to impurities present in the final benzil sample. Future experiments can accurately measure the melting point by ensuring the reaction system is not contaminated. Conclusion: The synthesis of phenytoin from benzaldehyde was successful. The % yield and melting point of benzil, weights of benzil and phenytoin as well as the appearance of phenytoin were successfully determined. The multistep Biltz’s method of synthesizing phenytoin from benzaldehyde is relatively easy to follow; caution however should be exercised during crystallization of benzoin because of the difficulty in forming benzoin crystals. References: 1. Gbaguidi, F. A., et al. "A high yield synthesis of phenytoin and relatecompounds using microwave activation ." African Journal of Pure and Applied Chemistry (2011): 168-175. . 2. Genome Alberta and Genome Canada. Phenytoin. 13 02 2013. 13 04 2013 . 3. Koreeda, M. "Experiment 5. Benzilic Acid Rearrangement: Preparation of Dilantin." 2011. < http://www.umich.edu/~chem216/216%20S11-Expt%205.pdf>. 4. Sigma-Aldrich. Benzil. 2013. 13 04 2013 . 5. Univesite De Geneve. "Benzoin condensation catalyzed by thiamine (n°38) ." 2011. < http://www.asso-etud.unige.ch/aecb/rapports/2eme/chiorg/p38cbenzoine_pacho.pdf>. Questions: 7.1. From the spectral database, the infrared spectrum of benzaldehyde has peaks at 2847cm-1and 2732 cm-1. These correspond to the C-H stretch in aldehydes. A prominent peak is visible at 1703 cm-1. This corresponds to a C=O stretch. A peak also exits at 1583 cm-1, this belongs to a C=C aromatic stretch. Benzoin, on the other hand, has a peak at 3407.0 cm-1 that corresponds to an O-H stretch. There is also a peak at 1679.21 cm-1 ­corresponding to a C=O aldehyde. The peak at 3066.26 cm-1 corresponds to an aromatic C=CH stretch. Benzaldehyde differs from benzoin because it lacks an O-H stretch at 3407.0 cm-1 8.1 The peaks in benzil observed in the infrared spectrum are a C=CH bond at 3062.41 cm-1, a C=O stretch at 1661.86 cm-1 and aromatic C=C bonds at 1595.81 cm-1. Benzil differs from benzoin because of the lack of an O-H stretch in benzil (at around 3407 cm-1). 9.1 The peaks in the phenytoin spectrum shows a peak at 1400.55 cm-1, this belongs to a C=C bond. Another peak exists at 1713.92 cm-1. This corresponds to a C=O stretch. The peak at 3069.64 cm-1 corresponds to a C=CH aromatic bond. The only way to distinguish between benzil from phenytoin is that benzil has two C=C stretches (at 1595.81 cm-1and 1661.86 cm-1) while phenytoin has one C=C stretch at 1400.55 cm-1. Read More